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John M. Maris - One of the best experts on this subject based on the ideXlab platform.

  • abstract c003 initial Testing of m276 pbd cd276 antibody drug conjugate in Preclinical models of pediatric cancers by the pediatric Preclinical Testing consortium pptc
    Molecular Cancer Therapeutics, 2019
    Co-Authors: Raushan T Kurmasheva, Kateryna Krytska, Stephen W. Erickson, Beverly A. Teicher, Malcom A. Smith, John M. Maris, Yael P. Mosse, Anders E Kolb, David Groff, Matthew Tang
    Abstract:

    Purpose: CD276 (B7-H3) is an immunoregulatory molecule that is reported to be widely expressed in pediatric embryonal tumors, pediatric sarcomas, and tumor infiltrating blood vessels. CD276 protein is expressed at low levels on several normal tissues, including cerebral cortex, liver and germinal lymph node. m276 is a fully-human IgG1 that binds with similar affinity to both mouse CD276 (24 nM kD) and human CD276 (29 nM kD) (Seaman et al., Cancer Cell, 2017). To generate an antibody-drug conjugate, m276 was site-specifically conjugated to the DNA damaging agent pyrrolobenzodiazepine (PBD) via a cleavable valine-alanine linker, providing m276-PBD with a Drug-to-Antibody Ratio (DAR) of 2. Here we examined the antitumor activity of m276-PBD against Preclinical xenograft models of pediatric solid tumors. Experimental Procedures: Expression of CD276 across PPTC xenograft models (>200) representing leukemias, brain tumors and solid tumors was determined by RNA seq, and additionally in neuroblastoma models by IHC. Xenograft experiments were undertaken in heterotopic models using standard methods of the PPTC. Response criteria were tumor regression (PR, CR, maintained CR [at 6 weeks]) and Event-Free Survival (EFS). m276-PBD was administered by intraperitoneal injection at a dose of 0.5 mg/kg, once weekly x 3 consecutive weeks. Results: CD276 expression was high in most solid tumors (median 41 FPKM) with highest expression in osteosarcoma. Neuroblastoma, rhabdomyosarcoma, Wilms tumor and embryonal brain tumor models had similar levels of expression, whereas ALL models showed low expression. In vivo efficacy studies are ongoing, but data to date are available for 5 osteosarcoma, 4 rhabdomyosarcoma, 2 Ewing sarcoma and 2 Wilms tumors. Maintained Complete Response (MCR) at 6 weeks was attained in 2/5 osteosarcoma, 3/4 rhabdomyosarcoma and 1/2 Ewing sarcoma. CR was achieved in 1/2 Wilms tumor, 1/2 rhabdomyosarcoma, and 2/5 osteosarcoma models. Body weight loss ( Citation Format: Raushan Kurmasheva, E. Anders Kolb, Malcolm A. Smith, Beverly A. Teicher, Stephen W. Erickson, John M. Maris, Yael P. Mosse, Kateryna Krytska, David Groff, Matthew Tang, Yifei Wang, Brad St. Croix, Richard Gorlick, Peter J. Houghton. Initial Testing of m276-PBD CD276 antibody-drug conjugate in Preclinical models of pediatric cancers by the Pediatric Preclinical Testing Consortium (PPTC) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C003. doi:10.1158/1535-7163.TARG-19-C003

  • pharmacodynamic and genomic markers associated with response to the xpo1 crm1 inhibitor selinexor kpt 330 a report from the pediatric Preclinical Testing program
    Pediatric Blood & Cancer, 2016
    Co-Authors: Edward F Attiyeh, John M. Maris, Anders E Kolb, Richard Gorlick, Richard B Lock, Hernan Carol, Stephen T Keir, Patrick C Reynolds, Min H Kang, Yosef Landesman
    Abstract:

    Background Selinexor (KPT-330) is an inhibitor of the major nuclear export receptor, exportin 1 (XPO1, also termed chromosome region maintenance 1, CRM1) that has demonstrated activity in Preclinical models and clinical activity against several solid and hematological cancers. Procedures Selinexor was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro cell line panel at concentrations from 1.0 nM to 10 μM and against the PPTP in vivo xenograft panels administered orally at a dose of 10 mg/kg thrice weekly for 4 weeks. Results Selinexor demonstrated cytotoxic activity in vitro, with a median relative IC50 value of 123 nM (range 13.0 nM to >10 μM). Selinexor induced significant differences in event-free survival (EFS) distribution in 29 of 38 (76%) of the evaluable solid tumor xenografts and in five of eight (63%) of the evaluable ALL xenografts. Objective responses (partial or complete responses, PR/CR) were observed for 4 of 38 solid tumor xenografts including Wilms tumor, medulloblastoma (n = 2), and ependymoma models. For the ALL panel, two of eight (25%) xenografts achieved either CR or maintained CR. Two responding xenografts had FBXW7 mutations at R465 and two had SMARCA4 mutations. Selinexor induced p53, p21, and cleaved PARP in several solid tumor models. Conclusions Selinexor induced regression against several solid tumor and ALL xenografts and slowed tumor growth in a larger number of models. Pharmacodynamic effects for XPO1 inhibition were noted. Defining the relationship between selinexor systemic exposures in mice and humans will be important in assessing the clinical relevance of these results. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.

  • abstract 1616 pharmacodynamic and genomic markers associated with response to the xpo1 crm1 inhibitor selinexor kpt 330 a report from the pediatric Preclinical Testing program
    Cancer Research, 2015
    Co-Authors: Malcolm A Smith, John M. Maris, Anders E Kolb, Richard Gorlick, Richard B Lock, Hernan Carol, Stephen T Keir, Yosef Landesman, Sharon Shacham, Dmitry Lyalin
    Abstract:

    Background: Selinexor (KPT-330) is an inhibitor of the major nuclear export receptor, exportin 1 (XPO1, also termed chromosome region maintenance 1 or CRM1) that has demonstrated activity in Preclinical models of several solid and hematological cancers. Procedures: Selinexor was tested against the PPTP in vivo xenograft panels administered orally at a dose of 10 mg/kg (3 times per week) for 4 weeks. For collection of specimens for pharmacodynamic Testing, KT-10 tumors that regressed rapidly after treatment with selinexor were harvested 24 hours after a single dose of drug (10 mg/kg). Other, less responsive tumors, were harvested 2 hours after dose 6 (MWF dosing) at 10 mg/kg/dose. Immunoblots were probed for p53, p21, PARP and cleaved PARP and XPO1/CRM1. IHC analysis was performed for a comparable set of proteins to assess nuclear localization. For exome sequencing, all mutations were verified and assessed as somatic using a virtual normal subtraction algorithm. Results: Objective responses (CRs) to selinexor were observed for 3 of 38 solid tumor xenografts including Wilms tumor (KT-10), medulloblastoma (BT-50) and ependymoma (BT-41) xenografts. For the ALL panel, 2 of 8 (25%) xenografts achieved either CR or MCR (ALL-8 and ALL-19). The mutation profiles for models with objective responses for which exome sequencing data were available (KT-10, BT-50, ALL-8 and ALL-19) were examined. The only recurring mutation was for FBXW7, with known oncogenic mutations identified for both BT-50 (R465H) and ALL-8 (R465C). One additional tested xenograft (ALL-31) had an FBXW7 mutation, but it was in the N-terminal region in the nuclear localization signal domain (c.45_46insCCT; p.15_16TR>TLR). KT-10 has a PALB2 mutation that leads to defective homologous recombination and to sensitivity to PARP inhibition. Selinexor induced a robust increase in p53 in KT-10 xenografts with PUMA induction and cleavage of PARP that was apparent after the first dose of drug, consistent with the rapid response of this tumor to treatment. Models that showed growth delay rather than regression showed a lesser induction of p53 and showed increased nuclear localization of a number of proteins (e.g., FOXO1, NFκB, and p53). Conclusions: Selinexor induced regression against several solid tumor and ALL xenografts, and slowed tumor growth for a larger number of models. Pharmacodynamic effects expected for XPO1 inhibition were noted in models without regard to tumor regression, although p53 induction was most robust in a highly sensitive Wilms tumor model. Exome sequencing identified potential genomic alterations (FBXW7 mutation and mutation in a homologous recombination gene) associated with sensitivity that require validation in a larger, independent set of tumors. Citation Format: Malcolm A. Smith, Richard Lock, Hernan Carol, John M. Maris, Richard Gorlick, E. Anders Kolb, Stephen T. Keir, Jianrong Wu, Yosef Landesman, Sharon Shacham, Dmitry Lyalin, Raushan T. Kurmasheva, Peter J. Houghton. Pharmacodynamic and genomic markers associated with response to the XPO1/CRM1 inhibitor selinexor (KPT-330): a report from the Pediatric Preclinical Testing Program. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1616. doi:10.1158/1538-7445.AM2015-1616

  • initial Testing stage 1 of the antibody maytansinoid conjugate imgn901 lorvotuzumab mertansine by the pediatric Preclinical Testing program
    Pediatric Blood & Cancer, 2013
    Co-Authors: Andrew C Wood, John M. Maris, Raushan T Kurmasheva, Anders E Kolb, Richard Gorlick, Stephen T Keir, Patrick C Reynolds, Min H Kang, Kathleen R Whiteman, Peter J Houghton
    Abstract:

    Background IMGN901 (lorvotuzumab mertansine) is an antibody-drug conjugate composed of a humanized antibody that specifically binds to CD56 (NCAM, neural cell adhesion molecule) and that is conjugated to the maytansinoid, DM1 (a microtubule targeting agent). Procedures IMGN901 and DM1-SMe (unconjugated DM1 as a mixed disulfide with thiomethane to cap its sulfhydryl group) were tested in vitro at concentrations ranging from 0.01 nM to 0.1 µM and 0.3 pM to 3 nM, respectively. IMGN901 was tested against a subset of PPTP solid tumor xenografts focusing on those with high CD56 expression.The combination of IMGN901 with topotecan was also evaluated. Results Neuroblastoma models expressed CD56 at or above the median expression level for all PPTP xenografts and cell lines. Neuroblastoma cell lines demonstrated relatively low sensitivity to DM1-SMe compared to other cell lines, but the sensitivity of neuroblastoma cell lines to IMGN901 was comparable to that of non-neuroblastoma cell lines. In vivo, objective responses were observed in 9 of 24 (38%) models including, three of seven neuroblastoma xenografts, and two of seven rhabdomyosarcoma xenografts. All xenografts with objective responses showed homogeneous high-level staining by IHC for CD56, but not all xenografts with homogenous high-level staining had objective responses. Combined with topotecan, IMGN901 demonstrated therapeutic enhancement against two of four neuroblastoma models. Conclusions IMGN901 has anti-tumor activity against some CD56 expressing pediatric cancer models. High expression of CD56 is a biomarker for in vivo response, but resistance mechanisms to IMGN901 in some high CD56 expressing lines need to be defined. Pediatr Blood Cancer 2013;60:1860–1867. © 2013 Wiley Periodicals, Inc.

  • initial Testing stage 1 of eribulin a novel tubulin binding agent by the pediatric Preclinical Testing program
    Pediatric Blood & Cancer, 2013
    Co-Authors: Anders E Kolb, John M. Maris, Richard Gorlick, Richard B Lock, Hernan Carol, Stephen T Keir, Patrick C Reynolds, Min H Kang, Catherine A Billups, Christopher Desjardins
    Abstract:

    Background Antimitotic agents are essential components for curative therapy of pediatric acute leukemias and many solid tumors. Eribulin is a novel agent that differs from both Vinca alkaloids and taxanes in its mode of binding to tubulin polymers. Procedures Eribulin was tested against the PPTP in vitro cell line panel at concentrations from 0.1 nM to 1.0 μM and against the PPTP in vivo xenograft panels at a dose of 1 mg/kg (solid tumors) or 1.5 mg/kg (ALL models) using a q4dx3 schedule repeated at Day 21. Results In vitro eribulin demonstrated cytotoxic activity, with a median relative IC50 value of 0.27 nM, (range <0.1–14.8 nM). Eribulin was well tolerated in vivo, and all 43 xenograft models were considered evaluable for efficacy. Eribulin induced significant differences in event-free survival (EFS) distribution compared to control in 29 of 35 (83%) of the solid tumors and in 8 of 8 (100%) of the ALL xenografts. Objective responses were observed in 18 of 35 (51%) solid tumor xenografts. Complete responses (CR) or maintained CR were observed in panels of Wilms tumor, Ewing sarcoma, rhabdomyosarcoma, glioblastoma, and osteosarcoma xenografts. All eight ALL xenografts achieved CR or MCR. Conclusions The high level of activity observed for eribulin against the PPTP Preclinical models makes this an interesting agent to consider for pediatric evaluation. The activity pattern observed for eribulin in the solid tumor panels is equal or superior to that observed previously for vincristine. Pediatr Blood Cancer 2013;601325-1332. © 2013 Wiley Periodicals, Inc.

Richard B Lock - One of the best experts on this subject based on the ideXlab platform.

  • abstract lb b16 the akr1c3 activated prodrug obi 3424 exerts profound in vivo efficacy against Preclinical models of t cell acute lymphoblastic leukemia t all a pediatric Preclinical Testing consortium study
    Molecular Cancer Therapeutics, 2018
    Co-Authors: Richard B Lock, Stephen W. Erickson, Beverly A. Teicher, Kathryn Evans, Raymond Yung, Tara Pritchard, Jianxin Duan, Malcolm A Smith
    Abstract:

    Introduction: Aldo-keto reductase family 1 member C3 (AKR1C3) belongs to a superfamily of oxidoreductases that are broadly expressed in human tissues. AKR1C3 catalyzes the reduction of a diverse group of substrates, and is expressed at high levels in several human cancers including T-ALL. We previously showed that AKR1C3 is a biomarker of T-ALL sensitivity to the hypoxia-activated pre-prodrug PR-104, which is also activated under aerobic conditions by AKR1C3 (Manesh et al, Blood, 2015;126:1193-202). Therefore, it was of interest to test the in vivo efficacy of OBI-3424 against Preclinical models of T-ALL, since OBI-3424 is a highly selective prodrug that is converted by AKR1C3 to a DNA alkylating agent. Methods: ALL patient-derived xenografts (PDXs) grew in an orthotopic manner following intravenous inoculation into NSG mice. Engraftment and response to treatment were assessed by enumeration of the % human leukemic blasts in the murine peripheral blood (%huCD45 + ). Treatment commenced when the %huCD45 + exceeded a median of 1%, and mice received OBI-3424 (2.5 mg/kg by the intraperitoneal route once weekly x 3) or vehicle. An event was defined as the %huCD45 + exceeding 25% or leukemia-related morbidity. The Kaplan-Meier method was used to compare event-free survival (EFS) between treated (T) and control (C) groups. Stringent objective response measures were assigned to each mouse and reported as group medians (Houghton et al, PBC, 2007;49:928-40). Leukemia infiltration into the femoral bone marrow was also assessed at Day 28 following treatment initiation. OBI-3424 was provided by Threshold Pharmaceutical and is being developed by OBI Pharma, Inc. (ex-Asia) and Ascenta Pharma (Asia). Results: OBI-3424 was well tolerated, with only a 2.8% toxicity rate in the drug-treated groups. OBI-3424 induced significant differences in EFS distribution compared to control in 9 of 9 (100%) of the evaluable PDXs. T-C values ranged from 17.1 to 65.2 days (T/C 2.3-14.0), and objective responses were observed in 8 of 9 PDXs (2 complete responses, CRs; 6 maintained CRs, MCRs). A significant reduction (P 37.3 days, T/C >3) compared with a CR for ALL-11/EV (T-C 21.1 days, T/C 2.5). Infiltration of ALL-11/1C3 cells into the murine bone marrow was significantly reduced at Day 28 in OBI-3424-treated compared with vehicle-treated mice (P Citation Format: Richard B. Lock, Kathryn Evans, Raymond Yung, Tara Pritchard, Beverly A. Teicher, JianXin Duan, Yuelong Guo, Stephen W. Erickson, Malcolm A. Smith. The AKR1C3-Activated Prodrug OBI-3424 Exerts Profound In Vivo Efficacy Against Preclinical Models of T-Cell Acute Lymphoblastic Leukemia (T-ALL); a Pediatric Preclinical Testing Consortium Study [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-B16.

  • pharmacodynamic and genomic markers associated with response to the xpo1 crm1 inhibitor selinexor kpt 330 a report from the pediatric Preclinical Testing program
    Pediatric Blood & Cancer, 2016
    Co-Authors: Edward F Attiyeh, John M. Maris, Anders E Kolb, Richard Gorlick, Richard B Lock, Hernan Carol, Stephen T Keir, Patrick C Reynolds, Min H Kang, Yosef Landesman
    Abstract:

    Background Selinexor (KPT-330) is an inhibitor of the major nuclear export receptor, exportin 1 (XPO1, also termed chromosome region maintenance 1, CRM1) that has demonstrated activity in Preclinical models and clinical activity against several solid and hematological cancers. Procedures Selinexor was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro cell line panel at concentrations from 1.0 nM to 10 μM and against the PPTP in vivo xenograft panels administered orally at a dose of 10 mg/kg thrice weekly for 4 weeks. Results Selinexor demonstrated cytotoxic activity in vitro, with a median relative IC50 value of 123 nM (range 13.0 nM to >10 μM). Selinexor induced significant differences in event-free survival (EFS) distribution in 29 of 38 (76%) of the evaluable solid tumor xenografts and in five of eight (63%) of the evaluable ALL xenografts. Objective responses (partial or complete responses, PR/CR) were observed for 4 of 38 solid tumor xenografts including Wilms tumor, medulloblastoma (n = 2), and ependymoma models. For the ALL panel, two of eight (25%) xenografts achieved either CR or maintained CR. Two responding xenografts had FBXW7 mutations at R465 and two had SMARCA4 mutations. Selinexor induced p53, p21, and cleaved PARP in several solid tumor models. Conclusions Selinexor induced regression against several solid tumor and ALL xenografts and slowed tumor growth in a larger number of models. Pharmacodynamic effects for XPO1 inhibition were noted. Defining the relationship between selinexor systemic exposures in mice and humans will be important in assessing the clinical relevance of these results. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.

  • abstract 1616 pharmacodynamic and genomic markers associated with response to the xpo1 crm1 inhibitor selinexor kpt 330 a report from the pediatric Preclinical Testing program
    Cancer Research, 2015
    Co-Authors: Malcolm A Smith, John M. Maris, Anders E Kolb, Richard Gorlick, Richard B Lock, Hernan Carol, Stephen T Keir, Yosef Landesman, Sharon Shacham, Dmitry Lyalin
    Abstract:

    Background: Selinexor (KPT-330) is an inhibitor of the major nuclear export receptor, exportin 1 (XPO1, also termed chromosome region maintenance 1 or CRM1) that has demonstrated activity in Preclinical models of several solid and hematological cancers. Procedures: Selinexor was tested against the PPTP in vivo xenograft panels administered orally at a dose of 10 mg/kg (3 times per week) for 4 weeks. For collection of specimens for pharmacodynamic Testing, KT-10 tumors that regressed rapidly after treatment with selinexor were harvested 24 hours after a single dose of drug (10 mg/kg). Other, less responsive tumors, were harvested 2 hours after dose 6 (MWF dosing) at 10 mg/kg/dose. Immunoblots were probed for p53, p21, PARP and cleaved PARP and XPO1/CRM1. IHC analysis was performed for a comparable set of proteins to assess nuclear localization. For exome sequencing, all mutations were verified and assessed as somatic using a virtual normal subtraction algorithm. Results: Objective responses (CRs) to selinexor were observed for 3 of 38 solid tumor xenografts including Wilms tumor (KT-10), medulloblastoma (BT-50) and ependymoma (BT-41) xenografts. For the ALL panel, 2 of 8 (25%) xenografts achieved either CR or MCR (ALL-8 and ALL-19). The mutation profiles for models with objective responses for which exome sequencing data were available (KT-10, BT-50, ALL-8 and ALL-19) were examined. The only recurring mutation was for FBXW7, with known oncogenic mutations identified for both BT-50 (R465H) and ALL-8 (R465C). One additional tested xenograft (ALL-31) had an FBXW7 mutation, but it was in the N-terminal region in the nuclear localization signal domain (c.45_46insCCT; p.15_16TR>TLR). KT-10 has a PALB2 mutation that leads to defective homologous recombination and to sensitivity to PARP inhibition. Selinexor induced a robust increase in p53 in KT-10 xenografts with PUMA induction and cleavage of PARP that was apparent after the first dose of drug, consistent with the rapid response of this tumor to treatment. Models that showed growth delay rather than regression showed a lesser induction of p53 and showed increased nuclear localization of a number of proteins (e.g., FOXO1, NFκB, and p53). Conclusions: Selinexor induced regression against several solid tumor and ALL xenografts, and slowed tumor growth for a larger number of models. Pharmacodynamic effects expected for XPO1 inhibition were noted in models without regard to tumor regression, although p53 induction was most robust in a highly sensitive Wilms tumor model. Exome sequencing identified potential genomic alterations (FBXW7 mutation and mutation in a homologous recombination gene) associated with sensitivity that require validation in a larger, independent set of tumors. Citation Format: Malcolm A. Smith, Richard Lock, Hernan Carol, John M. Maris, Richard Gorlick, E. Anders Kolb, Stephen T. Keir, Jianrong Wu, Yosef Landesman, Sharon Shacham, Dmitry Lyalin, Raushan T. Kurmasheva, Peter J. Houghton. Pharmacodynamic and genomic markers associated with response to the XPO1/CRM1 inhibitor selinexor (KPT-330): a report from the Pediatric Preclinical Testing Program. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1616. doi:10.1158/1538-7445.AM2015-1616

  • initial Testing stage 1 of eribulin a novel tubulin binding agent by the pediatric Preclinical Testing program
    Pediatric Blood & Cancer, 2013
    Co-Authors: Anders E Kolb, John M. Maris, Richard Gorlick, Richard B Lock, Hernan Carol, Stephen T Keir, Patrick C Reynolds, Min H Kang, Catherine A Billups, Christopher Desjardins
    Abstract:

    Background Antimitotic agents are essential components for curative therapy of pediatric acute leukemias and many solid tumors. Eribulin is a novel agent that differs from both Vinca alkaloids and taxanes in its mode of binding to tubulin polymers. Procedures Eribulin was tested against the PPTP in vitro cell line panel at concentrations from 0.1 nM to 1.0 μM and against the PPTP in vivo xenograft panels at a dose of 1 mg/kg (solid tumors) or 1.5 mg/kg (ALL models) using a q4dx3 schedule repeated at Day 21. Results In vitro eribulin demonstrated cytotoxic activity, with a median relative IC50 value of 0.27 nM, (range <0.1–14.8 nM). Eribulin was well tolerated in vivo, and all 43 xenograft models were considered evaluable for efficacy. Eribulin induced significant differences in event-free survival (EFS) distribution compared to control in 29 of 35 (83%) of the solid tumors and in 8 of 8 (100%) of the ALL xenografts. Objective responses were observed in 18 of 35 (51%) solid tumor xenografts. Complete responses (CR) or maintained CR were observed in panels of Wilms tumor, Ewing sarcoma, rhabdomyosarcoma, glioblastoma, and osteosarcoma xenografts. All eight ALL xenografts achieved CR or MCR. Conclusions The high level of activity observed for eribulin against the PPTP Preclinical models makes this an interesting agent to consider for pediatric evaluation. The activity pattern observed for eribulin in the solid tumor panels is equal or superior to that observed previously for vincristine. Pediatr Blood Cancer 2013;601325-1332. © 2013 Wiley Periodicals, Inc.

  • abstract lb 354 pediatric Preclinical Testing program pptp stage 1 evaluation of the xpo1 crm1 inhibitor kpt 330
    Cancer Research, 2013
    Co-Authors: Peter J Houghton, John M. Maris, Richard Gorlick, Richard B Lock, Hernan Carol, Stephen T Keir, Min H Kang, Patrick Reynolds, Anders Kolb, Catherine A Billups
    Abstract:

    Introduction: KPT-330 is an oral Selective Inhibitor of Nuclear Export (SINE) that binds covalently to XPO1 at Cys528 resulting in its irreversible inactivation. The nuclear export of over 200 proteins with specific nuclear export sequences (NES) is mediated via XPO1. Amongst the client proteins are many tumor suppressor and growth regulatory proteins (e.g., FOXO, IκB, pRb, p53, p73, p21, and p27). Methods: KPT-330 was tested against the PPTP9s in vitro cell line panel at concentrations ranging from 1.0 nM to 10.0 μM using the PPTP9s standard 96 hour exposure period. It was tested against the PPTP solid tumor xenografts using a dose of 10 mg/kg administered by the oral route thrice weekly (M-W-F) for 4 weeks with a total treatment/observation period of 6 weeks. Results: The median relative IC50 (rIC50) value for the PPTP cell lines was 125 nM, with a range from 13 nM to greater than 10 μM. There were no significant differences in rIC50 values by histotype, although there was a trend for greater sensitivity for the Ewing sarcoma cell lines (median rIC50 = 57 nM) and lesser sensitvity for the neuroblastoma cell lines (median rIC50 = 235 nM). Most cell lines showed Relative I/O% values between -75% and -100%, consistent with a prominent cytotoxic effect for KPT-330. KPT-330 was well tolerated in vivo. It induced significant differences in EFS distribution compared to control in 29 of 37 (78%) solid tumor xenografts and in 5 of 8 (63%) ALL xenografts. For those xenografts with a significant difference in EFS distribution between treated and control groups, an EFS T/C value of greater than 2.0 indicates a substantial agent effect in slowing tumor growth. KPT-330 induced this level of effect in 11 of 32 (34%) solid tumor xenografts, most frequently for the Wilms tumor (2 of 3) and the Ewing sarcoma (4 of 5) panels. Objective responses were observed in 3 of 38 (4%) solid tumor xenografts, including a maintained complete response (MCR) for a Wilms tumor xenograft, a CR for a medulloblastoma xenograft, and a CR for a slow-growing ependymoma xenograft. For the ALL panel, 2 of 8 (25%) xenografts achieved either CR (ALL-8, T-cell ALL) or MCR (ALL-19, B-precursor ALL). Conclusions: KPT-330 shows potent in vitro activity against many PPTP cell lines, consistent with the activation of multiple tumor suppressor proteins across diverse tumor genotypes. KPT-330 shows tumor regressing activity against selected PPTP solid tumor and ALL xenografts, and shows tumor growth inhibition for a larger number of models. Defining the relationship between KPT-330 systemic exposure in mice and humans will be important in assessing the clinical relevance of the PPTP in vivo results. Planned PD Testing may identify biomarkers associated with response of pediatric Preclinical models to KPT-330. KPT-330 is in phase 1 clinical trials in adults with advanced solid or hematological malignancies (NCT01607905 and NCT01607892). (Supported by NCI NO1-CM-42216) Citation Format: Peter Houghton, Min Kang, Patrick Reynolds, Richard Gorlick, Anders Kolb, John Maris, Stephen Keir, Hernan Carol, Richard Lock, Catherine Billups, Raushan Kurmasheva, Yosef Landesman, Sharon Shacham, Michael Kauffman, Malcolm A. Smith. Pediatric Preclinical Testing Program (PPTP) stage 1 evaluation of the XPO1/CRM1 inhibitor KPT-330. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-354. doi:10.1158/1538-7445.AM2013-LB-354

Malcolm A Smith - One of the best experts on this subject based on the ideXlab platform.

  • in vivo evaluation of the ezh2 inhibitor epz011989 alone or in combination with standard of care cytotoxic agents against pediatric malignant rhabdoid tumor Preclinical models a report from the pediatric Preclinical Testing consortium
    Pediatric Blood & Cancer, 2021
    Co-Authors: Raushan T Kurmasheva, Stephen W. Erickson, Malcolm A Smith, Eric J Earley, Peter J Houghton
    Abstract:

    The Pediatric Preclinical Testing Program (PPTP) previously reported the activity of the EZH2 inhibitor tazemetostat (EPZ6438) against xenograft models of rhabdoid tumors. Here, we determined whether an inhibitor of EZH2 enhanced the effect of standard of care chemotherapeutic agents: irinotecan, vincristine, and cyclophosphamide. EPZ011989 significantly prolonged time to event in all the six rhabdoid models studied but did not induce tumor regression. The addition of EPZ011989 to standard of care agents significantly improved time to event in at least one model for each of the agents studied, although this effect was observed in only a minority of the combination Testing experiments.

  • abstract lb b16 the akr1c3 activated prodrug obi 3424 exerts profound in vivo efficacy against Preclinical models of t cell acute lymphoblastic leukemia t all a pediatric Preclinical Testing consortium study
    Molecular Cancer Therapeutics, 2018
    Co-Authors: Richard B Lock, Stephen W. Erickson, Beverly A. Teicher, Kathryn Evans, Raymond Yung, Tara Pritchard, Jianxin Duan, Malcolm A Smith
    Abstract:

    Introduction: Aldo-keto reductase family 1 member C3 (AKR1C3) belongs to a superfamily of oxidoreductases that are broadly expressed in human tissues. AKR1C3 catalyzes the reduction of a diverse group of substrates, and is expressed at high levels in several human cancers including T-ALL. We previously showed that AKR1C3 is a biomarker of T-ALL sensitivity to the hypoxia-activated pre-prodrug PR-104, which is also activated under aerobic conditions by AKR1C3 (Manesh et al, Blood, 2015;126:1193-202). Therefore, it was of interest to test the in vivo efficacy of OBI-3424 against Preclinical models of T-ALL, since OBI-3424 is a highly selective prodrug that is converted by AKR1C3 to a DNA alkylating agent. Methods: ALL patient-derived xenografts (PDXs) grew in an orthotopic manner following intravenous inoculation into NSG mice. Engraftment and response to treatment were assessed by enumeration of the % human leukemic blasts in the murine peripheral blood (%huCD45 + ). Treatment commenced when the %huCD45 + exceeded a median of 1%, and mice received OBI-3424 (2.5 mg/kg by the intraperitoneal route once weekly x 3) or vehicle. An event was defined as the %huCD45 + exceeding 25% or leukemia-related morbidity. The Kaplan-Meier method was used to compare event-free survival (EFS) between treated (T) and control (C) groups. Stringent objective response measures were assigned to each mouse and reported as group medians (Houghton et al, PBC, 2007;49:928-40). Leukemia infiltration into the femoral bone marrow was also assessed at Day 28 following treatment initiation. OBI-3424 was provided by Threshold Pharmaceutical and is being developed by OBI Pharma, Inc. (ex-Asia) and Ascenta Pharma (Asia). Results: OBI-3424 was well tolerated, with only a 2.8% toxicity rate in the drug-treated groups. OBI-3424 induced significant differences in EFS distribution compared to control in 9 of 9 (100%) of the evaluable PDXs. T-C values ranged from 17.1 to 65.2 days (T/C 2.3-14.0), and objective responses were observed in 8 of 9 PDXs (2 complete responses, CRs; 6 maintained CRs, MCRs). A significant reduction (P 37.3 days, T/C >3) compared with a CR for ALL-11/EV (T-C 21.1 days, T/C 2.5). Infiltration of ALL-11/1C3 cells into the murine bone marrow was significantly reduced at Day 28 in OBI-3424-treated compared with vehicle-treated mice (P Citation Format: Richard B. Lock, Kathryn Evans, Raymond Yung, Tara Pritchard, Beverly A. Teicher, JianXin Duan, Yuelong Guo, Stephen W. Erickson, Malcolm A. Smith. The AKR1C3-Activated Prodrug OBI-3424 Exerts Profound In Vivo Efficacy Against Preclinical Models of T-Cell Acute Lymphoblastic Leukemia (T-ALL); a Pediatric Preclinical Testing Consortium Study [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-B16.

  • abstract 1616 pharmacodynamic and genomic markers associated with response to the xpo1 crm1 inhibitor selinexor kpt 330 a report from the pediatric Preclinical Testing program
    Cancer Research, 2015
    Co-Authors: Malcolm A Smith, John M. Maris, Anders E Kolb, Richard Gorlick, Richard B Lock, Hernan Carol, Stephen T Keir, Yosef Landesman, Sharon Shacham, Dmitry Lyalin
    Abstract:

    Background: Selinexor (KPT-330) is an inhibitor of the major nuclear export receptor, exportin 1 (XPO1, also termed chromosome region maintenance 1 or CRM1) that has demonstrated activity in Preclinical models of several solid and hematological cancers. Procedures: Selinexor was tested against the PPTP in vivo xenograft panels administered orally at a dose of 10 mg/kg (3 times per week) for 4 weeks. For collection of specimens for pharmacodynamic Testing, KT-10 tumors that regressed rapidly after treatment with selinexor were harvested 24 hours after a single dose of drug (10 mg/kg). Other, less responsive tumors, were harvested 2 hours after dose 6 (MWF dosing) at 10 mg/kg/dose. Immunoblots were probed for p53, p21, PARP and cleaved PARP and XPO1/CRM1. IHC analysis was performed for a comparable set of proteins to assess nuclear localization. For exome sequencing, all mutations were verified and assessed as somatic using a virtual normal subtraction algorithm. Results: Objective responses (CRs) to selinexor were observed for 3 of 38 solid tumor xenografts including Wilms tumor (KT-10), medulloblastoma (BT-50) and ependymoma (BT-41) xenografts. For the ALL panel, 2 of 8 (25%) xenografts achieved either CR or MCR (ALL-8 and ALL-19). The mutation profiles for models with objective responses for which exome sequencing data were available (KT-10, BT-50, ALL-8 and ALL-19) were examined. The only recurring mutation was for FBXW7, with known oncogenic mutations identified for both BT-50 (R465H) and ALL-8 (R465C). One additional tested xenograft (ALL-31) had an FBXW7 mutation, but it was in the N-terminal region in the nuclear localization signal domain (c.45_46insCCT; p.15_16TR>TLR). KT-10 has a PALB2 mutation that leads to defective homologous recombination and to sensitivity to PARP inhibition. Selinexor induced a robust increase in p53 in KT-10 xenografts with PUMA induction and cleavage of PARP that was apparent after the first dose of drug, consistent with the rapid response of this tumor to treatment. Models that showed growth delay rather than regression showed a lesser induction of p53 and showed increased nuclear localization of a number of proteins (e.g., FOXO1, NFκB, and p53). Conclusions: Selinexor induced regression against several solid tumor and ALL xenografts, and slowed tumor growth for a larger number of models. Pharmacodynamic effects expected for XPO1 inhibition were noted in models without regard to tumor regression, although p53 induction was most robust in a highly sensitive Wilms tumor model. Exome sequencing identified potential genomic alterations (FBXW7 mutation and mutation in a homologous recombination gene) associated with sensitivity that require validation in a larger, independent set of tumors. Citation Format: Malcolm A. Smith, Richard Lock, Hernan Carol, John M. Maris, Richard Gorlick, E. Anders Kolb, Stephen T. Keir, Jianrong Wu, Yosef Landesman, Sharon Shacham, Dmitry Lyalin, Raushan T. Kurmasheva, Peter J. Houghton. Pharmacodynamic and genomic markers associated with response to the XPO1/CRM1 inhibitor selinexor (KPT-330): a report from the Pediatric Preclinical Testing Program. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1616. doi:10.1158/1538-7445.AM2015-1616

  • initial Testing stage 1 of glembatumumab vedotin cdx 011 by the pediatric Preclinical Testing program
    Pediatric Blood & Cancer, 2014
    Co-Authors: Anders E Kolb, Raushan T Kurmasheva, Richard Gorlick, Peter J Houghton, Catherine A Billups, Thomas Hawthorne, Malcolm A Smith
    Abstract:

    Background Glembatumumab vedotin is an antibody-auristatin conjugate that targets cells expressing the transmembrane glycoprotein NMB (GPNMB, also known as osteoactivin). It has entered clinical evaluation for adult cancers that express GPNMB, including melanoma and breast cancer. Procedures Glembatumumab vedotin was administered intravenously at a dose of 2.5 mg/kg using a weekly × 3 schedule, and its antitumor activity was evaluated against selected Pediatric Preclinical Testing Program (PPTP) solid tumor xenografts using standard PPTP response metrics. Results Among PPTP xenografts, GPNMB was primarily expressed on the osteosarcoma xenografts, all of which expressed GPNMB at the RNA level, although at varying levels. Protein expression assessed by immunohistochemistry (IHC) showed variation across the osteosarcoma xenografts with one model showing no tumor cell expression. Glembatumumab vedotin induced statistically significant differences (P < 0.05) in event-free survival (EFS) distribution compared to control in each of the six osteosarcoma models studied. Three of six osteosarcoma xenografts demonstrated a maintained complete response (MCR). Two other xenografts showed progressive disease with growth delay, while the final xenograft showed progressive disease with no growth delay. Two of the osteosarcoma xenografts with MCRs showed the highest GPNMB expression at the RNA level. Conversely, the xenograft with the lowest GPNMB mRNA expression had the poorest response to glembatumumab vedotin. Two rhabdomyosarcoma xenografts that did not express GPNMB showed limited responses to glembatumumab vedotin. Conclusions Glembatumumab vedotin yielded high-level activity against three of six osteosarcoma xenografts, with evidence for response being related to GPNMB expression levels. Pediatr Blood Cancer 2014; 61:1816–1821. © 2014 Wiley Periodicals, Inc.

  • National Cancer Institute Pediatric Preclinical Testing Program: Model Description for In Vitro Cytotoxicity Testing
    Pediatric Blood & Cancer, 2010
    Co-Authors: Min H Kang, Christopher L Morton, Nino Keshelava, Peter J Houghton, Malcolm A Smith, C. Patrick Reynolds
    Abstract:

    Background The National Cancer Institute (NCI) has established the Pediatric Preclinical Testing Program (PPTP) for Testing drugs against in vitro and in vivo childhood cancer models to aid in the prioritization of drugs considered for early phase pediatric clinical trials. Procedures In vitro cytotoxicity Testing employs a semi-automated fluorescence-based digital imaging cytotoxicity assay (DIMSCAN) that has a 4-log dynamic range of detection. Curve fitting of the fractional survival data of the cell lines in response to various concentrations of the agents was used to calculate relative IC50, absolute IC50, and Ymin values. The panel of 23 pediatric cancer cell lines included leukemia (n = 6), lymphoma (n = 2), rhabdomyosarcoma (n = 4), brain tumors (n = 3), Ewing family of tumors (EFT, n = 4), and neuroblastoma (n = 4). The doubling times obtained using DIMSCAN were incorporated into data analyses to estimate the relationship between input cell numbers and final cell number. Results We report in vitro activity data for three drugs (vincristine, melphalan, and etoposide) that are commonly used for pediatric cancer and for the mTOR inhibitor rapamycin, an agent that is currently under Preclinical investigation for cancer. To date, the PPTP has completed in vitro Testing of 39 investigational and approved agents for single drug activity and two investigational agents in combination with various “standard” chemotherapy drugs. Conclusions This robust in vitro cytotoxicity Testing system for pediatric cancers will enable comparisons to response data for novel agents obtained from xenograft studies and from clinical trials. Pediatr Blood Cancer 2011;56:239–249. © 2010 Wiley-Liss, Inc.

Stephen T Keir - One of the best experts on this subject based on the ideXlab platform.

  • pharmacodynamic and genomic markers associated with response to the xpo1 crm1 inhibitor selinexor kpt 330 a report from the pediatric Preclinical Testing program
    Pediatric Blood & Cancer, 2016
    Co-Authors: Edward F Attiyeh, John M. Maris, Anders E Kolb, Richard Gorlick, Richard B Lock, Hernan Carol, Stephen T Keir, Patrick C Reynolds, Min H Kang, Yosef Landesman
    Abstract:

    Background Selinexor (KPT-330) is an inhibitor of the major nuclear export receptor, exportin 1 (XPO1, also termed chromosome region maintenance 1, CRM1) that has demonstrated activity in Preclinical models and clinical activity against several solid and hematological cancers. Procedures Selinexor was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro cell line panel at concentrations from 1.0 nM to 10 μM and against the PPTP in vivo xenograft panels administered orally at a dose of 10 mg/kg thrice weekly for 4 weeks. Results Selinexor demonstrated cytotoxic activity in vitro, with a median relative IC50 value of 123 nM (range 13.0 nM to >10 μM). Selinexor induced significant differences in event-free survival (EFS) distribution in 29 of 38 (76%) of the evaluable solid tumor xenografts and in five of eight (63%) of the evaluable ALL xenografts. Objective responses (partial or complete responses, PR/CR) were observed for 4 of 38 solid tumor xenografts including Wilms tumor, medulloblastoma (n = 2), and ependymoma models. For the ALL panel, two of eight (25%) xenografts achieved either CR or maintained CR. Two responding xenografts had FBXW7 mutations at R465 and two had SMARCA4 mutations. Selinexor induced p53, p21, and cleaved PARP in several solid tumor models. Conclusions Selinexor induced regression against several solid tumor and ALL xenografts and slowed tumor growth in a larger number of models. Pharmacodynamic effects for XPO1 inhibition were noted. Defining the relationship between selinexor systemic exposures in mice and humans will be important in assessing the clinical relevance of these results. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.

  • abstract 1616 pharmacodynamic and genomic markers associated with response to the xpo1 crm1 inhibitor selinexor kpt 330 a report from the pediatric Preclinical Testing program
    Cancer Research, 2015
    Co-Authors: Malcolm A Smith, John M. Maris, Anders E Kolb, Richard Gorlick, Richard B Lock, Hernan Carol, Stephen T Keir, Yosef Landesman, Sharon Shacham, Dmitry Lyalin
    Abstract:

    Background: Selinexor (KPT-330) is an inhibitor of the major nuclear export receptor, exportin 1 (XPO1, also termed chromosome region maintenance 1 or CRM1) that has demonstrated activity in Preclinical models of several solid and hematological cancers. Procedures: Selinexor was tested against the PPTP in vivo xenograft panels administered orally at a dose of 10 mg/kg (3 times per week) for 4 weeks. For collection of specimens for pharmacodynamic Testing, KT-10 tumors that regressed rapidly after treatment with selinexor were harvested 24 hours after a single dose of drug (10 mg/kg). Other, less responsive tumors, were harvested 2 hours after dose 6 (MWF dosing) at 10 mg/kg/dose. Immunoblots were probed for p53, p21, PARP and cleaved PARP and XPO1/CRM1. IHC analysis was performed for a comparable set of proteins to assess nuclear localization. For exome sequencing, all mutations were verified and assessed as somatic using a virtual normal subtraction algorithm. Results: Objective responses (CRs) to selinexor were observed for 3 of 38 solid tumor xenografts including Wilms tumor (KT-10), medulloblastoma (BT-50) and ependymoma (BT-41) xenografts. For the ALL panel, 2 of 8 (25%) xenografts achieved either CR or MCR (ALL-8 and ALL-19). The mutation profiles for models with objective responses for which exome sequencing data were available (KT-10, BT-50, ALL-8 and ALL-19) were examined. The only recurring mutation was for FBXW7, with known oncogenic mutations identified for both BT-50 (R465H) and ALL-8 (R465C). One additional tested xenograft (ALL-31) had an FBXW7 mutation, but it was in the N-terminal region in the nuclear localization signal domain (c.45_46insCCT; p.15_16TR>TLR). KT-10 has a PALB2 mutation that leads to defective homologous recombination and to sensitivity to PARP inhibition. Selinexor induced a robust increase in p53 in KT-10 xenografts with PUMA induction and cleavage of PARP that was apparent after the first dose of drug, consistent with the rapid response of this tumor to treatment. Models that showed growth delay rather than regression showed a lesser induction of p53 and showed increased nuclear localization of a number of proteins (e.g., FOXO1, NFκB, and p53). Conclusions: Selinexor induced regression against several solid tumor and ALL xenografts, and slowed tumor growth for a larger number of models. Pharmacodynamic effects expected for XPO1 inhibition were noted in models without regard to tumor regression, although p53 induction was most robust in a highly sensitive Wilms tumor model. Exome sequencing identified potential genomic alterations (FBXW7 mutation and mutation in a homologous recombination gene) associated with sensitivity that require validation in a larger, independent set of tumors. Citation Format: Malcolm A. Smith, Richard Lock, Hernan Carol, John M. Maris, Richard Gorlick, E. Anders Kolb, Stephen T. Keir, Jianrong Wu, Yosef Landesman, Sharon Shacham, Dmitry Lyalin, Raushan T. Kurmasheva, Peter J. Houghton. Pharmacodynamic and genomic markers associated with response to the XPO1/CRM1 inhibitor selinexor (KPT-330): a report from the Pediatric Preclinical Testing Program. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1616. doi:10.1158/1538-7445.AM2015-1616

  • initial Testing stage 1 of the antibody maytansinoid conjugate imgn901 lorvotuzumab mertansine by the pediatric Preclinical Testing program
    Pediatric Blood & Cancer, 2013
    Co-Authors: Andrew C Wood, John M. Maris, Raushan T Kurmasheva, Anders E Kolb, Richard Gorlick, Stephen T Keir, Patrick C Reynolds, Min H Kang, Kathleen R Whiteman, Peter J Houghton
    Abstract:

    Background IMGN901 (lorvotuzumab mertansine) is an antibody-drug conjugate composed of a humanized antibody that specifically binds to CD56 (NCAM, neural cell adhesion molecule) and that is conjugated to the maytansinoid, DM1 (a microtubule targeting agent). Procedures IMGN901 and DM1-SMe (unconjugated DM1 as a mixed disulfide with thiomethane to cap its sulfhydryl group) were tested in vitro at concentrations ranging from 0.01 nM to 0.1 µM and 0.3 pM to 3 nM, respectively. IMGN901 was tested against a subset of PPTP solid tumor xenografts focusing on those with high CD56 expression.The combination of IMGN901 with topotecan was also evaluated. Results Neuroblastoma models expressed CD56 at or above the median expression level for all PPTP xenografts and cell lines. Neuroblastoma cell lines demonstrated relatively low sensitivity to DM1-SMe compared to other cell lines, but the sensitivity of neuroblastoma cell lines to IMGN901 was comparable to that of non-neuroblastoma cell lines. In vivo, objective responses were observed in 9 of 24 (38%) models including, three of seven neuroblastoma xenografts, and two of seven rhabdomyosarcoma xenografts. All xenografts with objective responses showed homogeneous high-level staining by IHC for CD56, but not all xenografts with homogenous high-level staining had objective responses. Combined with topotecan, IMGN901 demonstrated therapeutic enhancement against two of four neuroblastoma models. Conclusions IMGN901 has anti-tumor activity against some CD56 expressing pediatric cancer models. High expression of CD56 is a biomarker for in vivo response, but resistance mechanisms to IMGN901 in some high CD56 expressing lines need to be defined. Pediatr Blood Cancer 2013;60:1860–1867. © 2013 Wiley Periodicals, Inc.

  • initial Testing stage 1 of eribulin a novel tubulin binding agent by the pediatric Preclinical Testing program
    Pediatric Blood & Cancer, 2013
    Co-Authors: Anders E Kolb, John M. Maris, Richard Gorlick, Richard B Lock, Hernan Carol, Stephen T Keir, Patrick C Reynolds, Min H Kang, Catherine A Billups, Christopher Desjardins
    Abstract:

    Background Antimitotic agents are essential components for curative therapy of pediatric acute leukemias and many solid tumors. Eribulin is a novel agent that differs from both Vinca alkaloids and taxanes in its mode of binding to tubulin polymers. Procedures Eribulin was tested against the PPTP in vitro cell line panel at concentrations from 0.1 nM to 1.0 μM and against the PPTP in vivo xenograft panels at a dose of 1 mg/kg (solid tumors) or 1.5 mg/kg (ALL models) using a q4dx3 schedule repeated at Day 21. Results In vitro eribulin demonstrated cytotoxic activity, with a median relative IC50 value of 0.27 nM, (range <0.1–14.8 nM). Eribulin was well tolerated in vivo, and all 43 xenograft models were considered evaluable for efficacy. Eribulin induced significant differences in event-free survival (EFS) distribution compared to control in 29 of 35 (83%) of the solid tumors and in 8 of 8 (100%) of the ALL xenografts. Objective responses were observed in 18 of 35 (51%) solid tumor xenografts. Complete responses (CR) or maintained CR were observed in panels of Wilms tumor, Ewing sarcoma, rhabdomyosarcoma, glioblastoma, and osteosarcoma xenografts. All eight ALL xenografts achieved CR or MCR. Conclusions The high level of activity observed for eribulin against the PPTP Preclinical models makes this an interesting agent to consider for pediatric evaluation. The activity pattern observed for eribulin in the solid tumor panels is equal or superior to that observed previously for vincristine. Pediatr Blood Cancer 2013;601325-1332. © 2013 Wiley Periodicals, Inc.

  • abstract lb 354 pediatric Preclinical Testing program pptp stage 1 evaluation of the xpo1 crm1 inhibitor kpt 330
    Cancer Research, 2013
    Co-Authors: Peter J Houghton, John M. Maris, Richard Gorlick, Richard B Lock, Hernan Carol, Stephen T Keir, Min H Kang, Patrick Reynolds, Anders Kolb, Catherine A Billups
    Abstract:

    Introduction: KPT-330 is an oral Selective Inhibitor of Nuclear Export (SINE) that binds covalently to XPO1 at Cys528 resulting in its irreversible inactivation. The nuclear export of over 200 proteins with specific nuclear export sequences (NES) is mediated via XPO1. Amongst the client proteins are many tumor suppressor and growth regulatory proteins (e.g., FOXO, IκB, pRb, p53, p73, p21, and p27). Methods: KPT-330 was tested against the PPTP9s in vitro cell line panel at concentrations ranging from 1.0 nM to 10.0 μM using the PPTP9s standard 96 hour exposure period. It was tested against the PPTP solid tumor xenografts using a dose of 10 mg/kg administered by the oral route thrice weekly (M-W-F) for 4 weeks with a total treatment/observation period of 6 weeks. Results: The median relative IC50 (rIC50) value for the PPTP cell lines was 125 nM, with a range from 13 nM to greater than 10 μM. There were no significant differences in rIC50 values by histotype, although there was a trend for greater sensitivity for the Ewing sarcoma cell lines (median rIC50 = 57 nM) and lesser sensitvity for the neuroblastoma cell lines (median rIC50 = 235 nM). Most cell lines showed Relative I/O% values between -75% and -100%, consistent with a prominent cytotoxic effect for KPT-330. KPT-330 was well tolerated in vivo. It induced significant differences in EFS distribution compared to control in 29 of 37 (78%) solid tumor xenografts and in 5 of 8 (63%) ALL xenografts. For those xenografts with a significant difference in EFS distribution between treated and control groups, an EFS T/C value of greater than 2.0 indicates a substantial agent effect in slowing tumor growth. KPT-330 induced this level of effect in 11 of 32 (34%) solid tumor xenografts, most frequently for the Wilms tumor (2 of 3) and the Ewing sarcoma (4 of 5) panels. Objective responses were observed in 3 of 38 (4%) solid tumor xenografts, including a maintained complete response (MCR) for a Wilms tumor xenograft, a CR for a medulloblastoma xenograft, and a CR for a slow-growing ependymoma xenograft. For the ALL panel, 2 of 8 (25%) xenografts achieved either CR (ALL-8, T-cell ALL) or MCR (ALL-19, B-precursor ALL). Conclusions: KPT-330 shows potent in vitro activity against many PPTP cell lines, consistent with the activation of multiple tumor suppressor proteins across diverse tumor genotypes. KPT-330 shows tumor regressing activity against selected PPTP solid tumor and ALL xenografts, and shows tumor growth inhibition for a larger number of models. Defining the relationship between KPT-330 systemic exposure in mice and humans will be important in assessing the clinical relevance of the PPTP in vivo results. Planned PD Testing may identify biomarkers associated with response of pediatric Preclinical models to KPT-330. KPT-330 is in phase 1 clinical trials in adults with advanced solid or hematological malignancies (NCT01607905 and NCT01607892). (Supported by NCI NO1-CM-42216) Citation Format: Peter Houghton, Min Kang, Patrick Reynolds, Richard Gorlick, Anders Kolb, John Maris, Stephen Keir, Hernan Carol, Richard Lock, Catherine Billups, Raushan Kurmasheva, Yosef Landesman, Sharon Shacham, Michael Kauffman, Malcolm A. Smith. Pediatric Preclinical Testing Program (PPTP) stage 1 evaluation of the XPO1/CRM1 inhibitor KPT-330. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-354. doi:10.1158/1538-7445.AM2013-LB-354

Richard Gorlick - One of the best experts on this subject based on the ideXlab platform.

  • pharmacodynamic and genomic markers associated with response to the xpo1 crm1 inhibitor selinexor kpt 330 a report from the pediatric Preclinical Testing program
    Pediatric Blood & Cancer, 2016
    Co-Authors: Edward F Attiyeh, John M. Maris, Anders E Kolb, Richard Gorlick, Richard B Lock, Hernan Carol, Stephen T Keir, Patrick C Reynolds, Min H Kang, Yosef Landesman
    Abstract:

    Background Selinexor (KPT-330) is an inhibitor of the major nuclear export receptor, exportin 1 (XPO1, also termed chromosome region maintenance 1, CRM1) that has demonstrated activity in Preclinical models and clinical activity against several solid and hematological cancers. Procedures Selinexor was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro cell line panel at concentrations from 1.0 nM to 10 μM and against the PPTP in vivo xenograft panels administered orally at a dose of 10 mg/kg thrice weekly for 4 weeks. Results Selinexor demonstrated cytotoxic activity in vitro, with a median relative IC50 value of 123 nM (range 13.0 nM to >10 μM). Selinexor induced significant differences in event-free survival (EFS) distribution in 29 of 38 (76%) of the evaluable solid tumor xenografts and in five of eight (63%) of the evaluable ALL xenografts. Objective responses (partial or complete responses, PR/CR) were observed for 4 of 38 solid tumor xenografts including Wilms tumor, medulloblastoma (n = 2), and ependymoma models. For the ALL panel, two of eight (25%) xenografts achieved either CR or maintained CR. Two responding xenografts had FBXW7 mutations at R465 and two had SMARCA4 mutations. Selinexor induced p53, p21, and cleaved PARP in several solid tumor models. Conclusions Selinexor induced regression against several solid tumor and ALL xenografts and slowed tumor growth in a larger number of models. Pharmacodynamic effects for XPO1 inhibition were noted. Defining the relationship between selinexor systemic exposures in mice and humans will be important in assessing the clinical relevance of these results. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.

  • abstract 1616 pharmacodynamic and genomic markers associated with response to the xpo1 crm1 inhibitor selinexor kpt 330 a report from the pediatric Preclinical Testing program
    Cancer Research, 2015
    Co-Authors: Malcolm A Smith, John M. Maris, Anders E Kolb, Richard Gorlick, Richard B Lock, Hernan Carol, Stephen T Keir, Yosef Landesman, Sharon Shacham, Dmitry Lyalin
    Abstract:

    Background: Selinexor (KPT-330) is an inhibitor of the major nuclear export receptor, exportin 1 (XPO1, also termed chromosome region maintenance 1 or CRM1) that has demonstrated activity in Preclinical models of several solid and hematological cancers. Procedures: Selinexor was tested against the PPTP in vivo xenograft panels administered orally at a dose of 10 mg/kg (3 times per week) for 4 weeks. For collection of specimens for pharmacodynamic Testing, KT-10 tumors that regressed rapidly after treatment with selinexor were harvested 24 hours after a single dose of drug (10 mg/kg). Other, less responsive tumors, were harvested 2 hours after dose 6 (MWF dosing) at 10 mg/kg/dose. Immunoblots were probed for p53, p21, PARP and cleaved PARP and XPO1/CRM1. IHC analysis was performed for a comparable set of proteins to assess nuclear localization. For exome sequencing, all mutations were verified and assessed as somatic using a virtual normal subtraction algorithm. Results: Objective responses (CRs) to selinexor were observed for 3 of 38 solid tumor xenografts including Wilms tumor (KT-10), medulloblastoma (BT-50) and ependymoma (BT-41) xenografts. For the ALL panel, 2 of 8 (25%) xenografts achieved either CR or MCR (ALL-8 and ALL-19). The mutation profiles for models with objective responses for which exome sequencing data were available (KT-10, BT-50, ALL-8 and ALL-19) were examined. The only recurring mutation was for FBXW7, with known oncogenic mutations identified for both BT-50 (R465H) and ALL-8 (R465C). One additional tested xenograft (ALL-31) had an FBXW7 mutation, but it was in the N-terminal region in the nuclear localization signal domain (c.45_46insCCT; p.15_16TR>TLR). KT-10 has a PALB2 mutation that leads to defective homologous recombination and to sensitivity to PARP inhibition. Selinexor induced a robust increase in p53 in KT-10 xenografts with PUMA induction and cleavage of PARP that was apparent after the first dose of drug, consistent with the rapid response of this tumor to treatment. Models that showed growth delay rather than regression showed a lesser induction of p53 and showed increased nuclear localization of a number of proteins (e.g., FOXO1, NFκB, and p53). Conclusions: Selinexor induced regression against several solid tumor and ALL xenografts, and slowed tumor growth for a larger number of models. Pharmacodynamic effects expected for XPO1 inhibition were noted in models without regard to tumor regression, although p53 induction was most robust in a highly sensitive Wilms tumor model. Exome sequencing identified potential genomic alterations (FBXW7 mutation and mutation in a homologous recombination gene) associated with sensitivity that require validation in a larger, independent set of tumors. Citation Format: Malcolm A. Smith, Richard Lock, Hernan Carol, John M. Maris, Richard Gorlick, E. Anders Kolb, Stephen T. Keir, Jianrong Wu, Yosef Landesman, Sharon Shacham, Dmitry Lyalin, Raushan T. Kurmasheva, Peter J. Houghton. Pharmacodynamic and genomic markers associated with response to the XPO1/CRM1 inhibitor selinexor (KPT-330): a report from the Pediatric Preclinical Testing Program. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1616. doi:10.1158/1538-7445.AM2015-1616

  • initial Testing stage 1 of glembatumumab vedotin cdx 011 by the pediatric Preclinical Testing program
    Pediatric Blood & Cancer, 2014
    Co-Authors: Anders E Kolb, Raushan T Kurmasheva, Richard Gorlick, Peter J Houghton, Catherine A Billups, Thomas Hawthorne, Malcolm A Smith
    Abstract:

    Background Glembatumumab vedotin is an antibody-auristatin conjugate that targets cells expressing the transmembrane glycoprotein NMB (GPNMB, also known as osteoactivin). It has entered clinical evaluation for adult cancers that express GPNMB, including melanoma and breast cancer. Procedures Glembatumumab vedotin was administered intravenously at a dose of 2.5 mg/kg using a weekly × 3 schedule, and its antitumor activity was evaluated against selected Pediatric Preclinical Testing Program (PPTP) solid tumor xenografts using standard PPTP response metrics. Results Among PPTP xenografts, GPNMB was primarily expressed on the osteosarcoma xenografts, all of which expressed GPNMB at the RNA level, although at varying levels. Protein expression assessed by immunohistochemistry (IHC) showed variation across the osteosarcoma xenografts with one model showing no tumor cell expression. Glembatumumab vedotin induced statistically significant differences (P < 0.05) in event-free survival (EFS) distribution compared to control in each of the six osteosarcoma models studied. Three of six osteosarcoma xenografts demonstrated a maintained complete response (MCR). Two other xenografts showed progressive disease with growth delay, while the final xenograft showed progressive disease with no growth delay. Two of the osteosarcoma xenografts with MCRs showed the highest GPNMB expression at the RNA level. Conversely, the xenograft with the lowest GPNMB mRNA expression had the poorest response to glembatumumab vedotin. Two rhabdomyosarcoma xenografts that did not express GPNMB showed limited responses to glembatumumab vedotin. Conclusions Glembatumumab vedotin yielded high-level activity against three of six osteosarcoma xenografts, with evidence for response being related to GPNMB expression levels. Pediatr Blood Cancer 2014; 61:1816–1821. © 2014 Wiley Periodicals, Inc.

  • initial Testing stage 1 of the antibody maytansinoid conjugate imgn901 lorvotuzumab mertansine by the pediatric Preclinical Testing program
    Pediatric Blood & Cancer, 2013
    Co-Authors: Andrew C Wood, John M. Maris, Raushan T Kurmasheva, Anders E Kolb, Richard Gorlick, Stephen T Keir, Patrick C Reynolds, Min H Kang, Kathleen R Whiteman, Peter J Houghton
    Abstract:

    Background IMGN901 (lorvotuzumab mertansine) is an antibody-drug conjugate composed of a humanized antibody that specifically binds to CD56 (NCAM, neural cell adhesion molecule) and that is conjugated to the maytansinoid, DM1 (a microtubule targeting agent). Procedures IMGN901 and DM1-SMe (unconjugated DM1 as a mixed disulfide with thiomethane to cap its sulfhydryl group) were tested in vitro at concentrations ranging from 0.01 nM to 0.1 µM and 0.3 pM to 3 nM, respectively. IMGN901 was tested against a subset of PPTP solid tumor xenografts focusing on those with high CD56 expression.The combination of IMGN901 with topotecan was also evaluated. Results Neuroblastoma models expressed CD56 at or above the median expression level for all PPTP xenografts and cell lines. Neuroblastoma cell lines demonstrated relatively low sensitivity to DM1-SMe compared to other cell lines, but the sensitivity of neuroblastoma cell lines to IMGN901 was comparable to that of non-neuroblastoma cell lines. In vivo, objective responses were observed in 9 of 24 (38%) models including, three of seven neuroblastoma xenografts, and two of seven rhabdomyosarcoma xenografts. All xenografts with objective responses showed homogeneous high-level staining by IHC for CD56, but not all xenografts with homogenous high-level staining had objective responses. Combined with topotecan, IMGN901 demonstrated therapeutic enhancement against two of four neuroblastoma models. Conclusions IMGN901 has anti-tumor activity against some CD56 expressing pediatric cancer models. High expression of CD56 is a biomarker for in vivo response, but resistance mechanisms to IMGN901 in some high CD56 expressing lines need to be defined. Pediatr Blood Cancer 2013;60:1860–1867. © 2013 Wiley Periodicals, Inc.

  • initial Testing stage 1 of eribulin a novel tubulin binding agent by the pediatric Preclinical Testing program
    Pediatric Blood & Cancer, 2013
    Co-Authors: Anders E Kolb, John M. Maris, Richard Gorlick, Richard B Lock, Hernan Carol, Stephen T Keir, Patrick C Reynolds, Min H Kang, Catherine A Billups, Christopher Desjardins
    Abstract:

    Background Antimitotic agents are essential components for curative therapy of pediatric acute leukemias and many solid tumors. Eribulin is a novel agent that differs from both Vinca alkaloids and taxanes in its mode of binding to tubulin polymers. Procedures Eribulin was tested against the PPTP in vitro cell line panel at concentrations from 0.1 nM to 1.0 μM and against the PPTP in vivo xenograft panels at a dose of 1 mg/kg (solid tumors) or 1.5 mg/kg (ALL models) using a q4dx3 schedule repeated at Day 21. Results In vitro eribulin demonstrated cytotoxic activity, with a median relative IC50 value of 0.27 nM, (range <0.1–14.8 nM). Eribulin was well tolerated in vivo, and all 43 xenograft models were considered evaluable for efficacy. Eribulin induced significant differences in event-free survival (EFS) distribution compared to control in 29 of 35 (83%) of the solid tumors and in 8 of 8 (100%) of the ALL xenografts. Objective responses were observed in 18 of 35 (51%) solid tumor xenografts. Complete responses (CR) or maintained CR were observed in panels of Wilms tumor, Ewing sarcoma, rhabdomyosarcoma, glioblastoma, and osteosarcoma xenografts. All eight ALL xenografts achieved CR or MCR. Conclusions The high level of activity observed for eribulin against the PPTP Preclinical models makes this an interesting agent to consider for pediatric evaluation. The activity pattern observed for eribulin in the solid tumor panels is equal or superior to that observed previously for vincristine. Pediatr Blood Cancer 2013;601325-1332. © 2013 Wiley Periodicals, Inc.