The Experts below are selected from a list of 174 Experts worldwide ranked by ideXlab platform

Christopher P. Leamon - One of the best experts on this subject based on the ideXlab platform.

  • Pre-clinical evaluation of EC1456, a folate-tubulysin anti-cancer therapeutic
    Scientific Reports, 2018
    Co-Authors: Joseph A. Reddy, Alicia Bloomfield, Ryan Dorton, Marilynn Vetzel, Melissa Nelson, Iontcho R. Vlahov, Christina Dircksen, Paul Kleindl, Hari Santhapuram, Christopher P. Leamon
    Abstract:

    EC1456 is a folate-tubulysin conjugate constructed with an all-D enantiomeric spacer/linker configuration. When tested against folate receptor (FR)-positive cells, EC1456 demonstrated dose-responsive activity with an approximate 1000-fold level of specificity. Treatment of nude mice bearing FR-positive human xenografts (as large as 800 mm^3) with non-toxic doses of EC1456 led to cures in 100% of the mice. Combinations of low dose EC1456 with standard of care agents such as platins, taxanes, topotecan and bevacizumab, safely and significantly augmented the growth inhibitory effects of these commonly used agents. When tested against FR-positive human tumor xenograft models having confirmed resistance to a folate-vinca alkaloid (Vintafolide), cisplatin or paclitaxel, EC1456 was found to generate partial to curative responses. Taken together, these studies demonstrate that EC1456 has significant anti-proliferative activity against FR-positive tumors, including models which were anticancer drug resistant, thereby justifying a Phase 1 trial of this agent for the treatment of advanced human cancers.

  • Abstract 2133: Pre-clinical studies of EC2629, a highly potent FR targeted DNA crosslinking agent
    Experimental and Molecular Therapeutics, 2017
    Co-Authors: Joseph A. Reddy, Marilynn Vetzel, Melissa Nelson, Iontcho R. Vlahov, Christina Dircksen, Theresa Johnson, Spencer Hahn, Christopher P. Leamon
    Abstract:

    Folate receptor (FR) targeted small molecule drug conjugates (SMDCs) have shown promising results in early stage clinical trials with Vintafolide and EC1456. In our effort to develop FR targeted SMDCs with varying mechanisms of action, we have now built EC2629, a folate conjugate of a DNA crosslinking agent based on a novel DNA-alkylating moiety . This agent was found to be extremely potent with an in vitro IC50 ~ 100 x lower than any other folate SMDC we have created to date. Treatment of nude mice bearing FR positive human xenografts led to cures in 100% of the mice at very low doses (300 nmol/kg) using a convenient once a week schedule. The observed activity was not accompanied by any noticeable weight loss (up to 20 weeks post end of dosing) or major organ tissue degeneration. Complete responses were also observed in other FR-positive drug resistant (paclitaxel and cisplatin) models. When evaluated against FR-positive PDX models of ovarian, endometrial and triple negative breast (TNBC) cancers, EC2629 showed significantly greater anti-tumor activity than EC1456 or standard of care (SOC) treatments. Taken together, these studies demonstrated that EC2629 with a distinct DNA reacting mechanism has significant anti-tumor growth activity in numerous models, including those which were drug resistant, thus lending support to our planned clinical development of this novel FR-targeted agent. Citation Format: Joseph A. Reddy, Melissa Nelson, Christina Dircksen, Theresa Johnson, Marilynn Vetzel, Spencer Hahn, Longwu Qi, Iontcho Vlahov, Christopher Leamon. Pre-clinical studies of EC2629, a highly potent FR targeted DNA crosslinking agent [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2133. doi:10.1158/1538-7445.AM2017-2133

  • Abstract 3754: Pre-clinical studies of a highly potent folate receptor targeted DNA crosslinking agent
    Experimental and Molecular Therapeutics, 2016
    Co-Authors: Joseph A. Reddy, Marilynn Vetzel, Melissa Nelson, Iontcho R. Vlahov, Theresa Johnson, Spencer Hahn, Christina Dirksen, Christopher P. Leamon
    Abstract:

    Folate receptor (FR) targeted small molecule drug conjugates (SMDC) have shown promising results in early stage clinical trials with Vintafolide and EC1456. In our effort to develop FR targeted SMDCs with varying mechanisms of action, we have now built a folate conjugate of a DNA crosslinking agent based on a novel DNA-alkylating moiety. This agent was found to be extremely potent with an in vitro IC50 ∼ 100 x lower than any other folate SMDC we have created to date. Treatment of nude mice bearing FR positive human xenografts led to cures in 100% of the mice at very low doses (> 500 nmol/kg) and a convenient once a week schedule. The observed activity was not accompanied by any noticeable weight loss (up to 20 weeks post end of dosing) or major organ tissue degeneration. In contrast, no significant anti-tumor activity (0% CR’s) was observed in treated animals that were co-dosed with an excess of a benign folate ligand, thus demonstrating its target-specific activity. Complete responses were also observed in other FR positive drug resistant (paclitaxel and cisplatin) models. Taken together, these studies demonstrated that this SMDC with a distinct DNA reacting mechanism has significant anti-tumor growth activity and tolerability, thus lending support to future clinical development of this novel FR-targeted agent. Citation Format: Joseph A. Reddy, Melissa Nelson, Theresa Johnson, Christina Dirksen, Marilynn Vetzel, Spencer Hahn, LongWu Qi, Iontcho Vlahov, Christopher Leamon. Pre-clinical studies of a highly potent folate receptor targeted DNA crosslinking agent. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3754.

  • Abstract 4488: Folate receptor targeted therapy using small molecule drug conjugates constructed with high affinity antifolate ligands
    Experimental and Molecular Therapeutics, 2015
    Co-Authors: Christopher P. Leamon, Joseph A. Reddy, Marilynn Vetzel, Melissa Nelson, Iontcho R. Vlahov, Fei You, Paul J. Kleindl, Patrick J. Klein, Hanna F. Klein, Larry H Matherly
    Abstract:

    Folate receptor (FR)-targeted small molecule drug conjugates (SMDC) have shown promising clinical results. To date, all related SMDCs have been constructed with folic acid. Whereas folic acid displays very high affinity for the FR (kd ∼ 0.1 nM), antifolates with similar high binding affinity and specificity have also been reported. This knowledge prompted our investigation towards substituting the folic acid targeting moiety in our SMDCs with high affinity antifolates, such as CB3717 (a thymidylate synthase inhibitor), and the glycinamide ribonucleotide formyltransferase (GARFTase) inhibitors, AG94 and AG147, thereby testing the hypothesis that greater antitumor activity should result from the combination of inhibitors. Using mice bearing FR-positive human tumor xenografts, we observed curative activity with a CB3717-based vinca alkaloid SMDC under conditions where no cures resulted with Vintafolide (EC145) treatment. Similarly, tubulysin SMDCs constructed with AG94 and AG147 were found to produce curative activity using a dosing regimen where a folic acid-tubulysin conjugate did not. Of note, treatment of mice with simple co-mixtures of the antifolates and untargeted drugs was found to be ineffective, thereby confirming the need for linking the two moieties together to produce maximal activity. Taken together, these studies demonstrate that high affinity antifolates can be used in an SMDC format serving as both a high affinity targeting ligand and as a second drug having different, and perhaps a complementary mechanism of action to yield greater antitumor activity. Citation Format: Christopher P. Leamon, Joseph A. Reddy, Iontcho R. Vlahov, Fei You, Hanna F. Klein, Paul J. Kleindl, Melissa Nelson, Marilynn Vetzel, Patrick J. Klein, Larry H. Matherly, Aleem Gangjee. Folate receptor targeted therapy using small molecule drug conjugates constructed with high affinity antifolate ligands. [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 4488. doi:10.1158/1538-7445.AM2015-4488

  • Vintafolide: a novel targeted therapy for the treatment of folate receptor expressing tumors.
    Therapeutic advances in medical oncology, 2015
    Co-Authors: Ignace Vergote, Christopher P. Leamon
    Abstract:

    Despite advances in the development of molecularly targeted therapies, limited improvements in overall survival have been noted among many cancer patients with solid tumors, primarily due to development of drug resistance. Accordingly, there is an unmet need for new targeted therapies and treatment approaches for cancer, especially for overcoming resistance. Expression of the folate receptor is upregulated in many tumor types and thus represents an ideal target for cancer treatment. Several folate receptor targeted therapies are in development, including the small molecule drug conjugate Vintafolide, the monoclonal antibody farletuzumab, and the antibody-drug conjugate IMGN853. The role of the folate receptor as a target in cancer progression and resistance as well as emerging preclinical and clinical data from studies on those folate receptor targeted agents that are in development with a focus on Vintafolide are reviewed. The folate receptor has several unique properties, such as high expression in several tumor types, that make it a rational target for cancer treatment, and allow for selective delivery of folate receptor targeted agents. Early-stage clinical data in lung and ovarian cancer suggest that Vintafolide has the potential for combination with other standard approved agents.

Joseph A. Reddy - One of the best experts on this subject based on the ideXlab platform.

  • Pre-clinical studies of EC2629, a highly potent folate- receptor-targeted DNA crosslinking agent
    Scientific Reports, 2020
    Co-Authors: Joseph A. Reddy, Marilynn Vetzel, Melissa Nelson, Hari Krishna Santhapuram, Christina Dircksen, Theresa Johnson, Vicky Cross, Elaine Westrick, Spencer Hahn, Garth Parham
    Abstract:

    Folate receptor (FR)-targeted small molecule drug conjugates (SMDCs) have shown promising results in early stage clinical trials with microtubule destabilizing agents, such as Vintafolide and EC1456. In our effort to develop FR-targeted SMDCs with varying mechanisms of action, we synthesized EC2629, a folate conjugate of a DNA crosslinking agent based on a novel DNA-alkylating moiety. This agent was found to be extremely potent with an in vitro IC50 ~ 100× lower than folate SMDCs constructed with various microtubule inhibitors. EC2629 treatment of nude mice bearing FR-positive KB human xenografts led to cures in 100% of the test animals with very low dose levels (300 nmol/kg) following a convenient once a week schedule. The observed activity was not accompanied by any noticeable weight loss (up to 20 weeks post end of dosing). Complete responses were also observed against FR-positive paclitaxel (KB-PR) and cisplatin (KB-CR) resistant models. When evaluated against FR-positive patient derived xenograft (PDX) models of ovarian (ST070), endometrial (ST040) and triple negative breast cancers (ST502, ST738), EC2629 showed significantly greater anti-tumor activity compared to their corresponding standard of care treatments. Taken together, these studies thus demonstrated that EC2629, with its distinct DNA reacting mechanism, may be useful in treating FR-positive tumors, including those that are classified as drug resistant.

  • Pre-clinical evaluation of EC1456, a folate-tubulysin anti-cancer therapeutic
    Scientific Reports, 2018
    Co-Authors: Joseph A. Reddy, Alicia Bloomfield, Ryan Dorton, Marilynn Vetzel, Melissa Nelson, Iontcho R. Vlahov, Christina Dircksen, Paul Kleindl, Hari Santhapuram, Christopher P. Leamon
    Abstract:

    EC1456 is a folate-tubulysin conjugate constructed with an all-D enantiomeric spacer/linker configuration. When tested against folate receptor (FR)-positive cells, EC1456 demonstrated dose-responsive activity with an approximate 1000-fold level of specificity. Treatment of nude mice bearing FR-positive human xenografts (as large as 800 mm^3) with non-toxic doses of EC1456 led to cures in 100% of the mice. Combinations of low dose EC1456 with standard of care agents such as platins, taxanes, topotecan and bevacizumab, safely and significantly augmented the growth inhibitory effects of these commonly used agents. When tested against FR-positive human tumor xenograft models having confirmed resistance to a folate-vinca alkaloid (Vintafolide), cisplatin or paclitaxel, EC1456 was found to generate partial to curative responses. Taken together, these studies demonstrate that EC1456 has significant anti-proliferative activity against FR-positive tumors, including models which were anticancer drug resistant, thereby justifying a Phase 1 trial of this agent for the treatment of advanced human cancers.

  • Abstract 2133: Pre-clinical studies of EC2629, a highly potent FR targeted DNA crosslinking agent
    Experimental and Molecular Therapeutics, 2017
    Co-Authors: Joseph A. Reddy, Marilynn Vetzel, Melissa Nelson, Iontcho R. Vlahov, Christina Dircksen, Theresa Johnson, Spencer Hahn, Christopher P. Leamon
    Abstract:

    Folate receptor (FR) targeted small molecule drug conjugates (SMDCs) have shown promising results in early stage clinical trials with Vintafolide and EC1456. In our effort to develop FR targeted SMDCs with varying mechanisms of action, we have now built EC2629, a folate conjugate of a DNA crosslinking agent based on a novel DNA-alkylating moiety . This agent was found to be extremely potent with an in vitro IC50 ~ 100 x lower than any other folate SMDC we have created to date. Treatment of nude mice bearing FR positive human xenografts led to cures in 100% of the mice at very low doses (300 nmol/kg) using a convenient once a week schedule. The observed activity was not accompanied by any noticeable weight loss (up to 20 weeks post end of dosing) or major organ tissue degeneration. Complete responses were also observed in other FR-positive drug resistant (paclitaxel and cisplatin) models. When evaluated against FR-positive PDX models of ovarian, endometrial and triple negative breast (TNBC) cancers, EC2629 showed significantly greater anti-tumor activity than EC1456 or standard of care (SOC) treatments. Taken together, these studies demonstrated that EC2629 with a distinct DNA reacting mechanism has significant anti-tumor growth activity in numerous models, including those which were drug resistant, thus lending support to our planned clinical development of this novel FR-targeted agent. Citation Format: Joseph A. Reddy, Melissa Nelson, Christina Dircksen, Theresa Johnson, Marilynn Vetzel, Spencer Hahn, Longwu Qi, Iontcho Vlahov, Christopher Leamon. Pre-clinical studies of EC2629, a highly potent FR targeted DNA crosslinking agent [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2133. doi:10.1158/1538-7445.AM2017-2133

  • high levels of expression of p glycoprotein multidrug resistance protein result in resistance to Vintafolide
    Molecular Cancer Therapeutics, 2016
    Co-Authors: Amy D. Guertin, Joseph A. Reddy, Alicia Bloomfield, Ryan Dorton, Brian B. Haines, Marlene C. Hinton, Jennifer Oneil, Alexander Stoeck, Razvan Cristescu, Melissa Nelson
    Abstract:

    Targeting surface receptors overexpressed on cancer cells is one way to specifically treat cancer versus normal cells. Vintafolide (EC145), which consists of folate linked to a cytotoxic small molecule, desacetylvinblastine hydrazide (DAVLBH), takes advantage of the overexpression of folate receptor (FR) on cancer cells. Once bound to FR, Vintafolide enters the cell by endocytosis, and the reducing environment of the endosome cleaves the linker, releasing DAVLBH to destabilize microtubules. Vintafolide has shown efficacy and improved tolerability compared with DAVLBH in FR-positive preclinical models. As the first FR-targeting drug to reach the clinic, Vintafolide has achieved favorable responses in phase II clinical trials in FR-positive ovarian and lung cancer. However, some FR-positive patients in these clinical trials do not respond to Vintafolide. We sought to identify potential biomarkers of resistance to aid in the future development of this and other FR-targeting drugs. Here, we confirm that high P-glycoprotein (P-gp) expression was the strongest predictor of resistance to DAVLBH in a panel of 359 cancer cell lines. Furthermore, targeted delivery of DAVLBH via the FR, as in Vintafolide, fails to overcome P-gp-mediated efflux of DAVLBH in both in vitro and in vivo preclinical models. Therefore, we suggest that patients whose tumors express high levels of P-gp be excluded from future clinical trials for Vintafolide as well as other FR-targeted therapeutics bearing a P-gp substrate. Mol Cancer Ther; 15(8); 1998-2008. ©2016 AACR.

  • Abstract 3754: Pre-clinical studies of a highly potent folate receptor targeted DNA crosslinking agent
    Experimental and Molecular Therapeutics, 2016
    Co-Authors: Joseph A. Reddy, Marilynn Vetzel, Melissa Nelson, Iontcho R. Vlahov, Theresa Johnson, Spencer Hahn, Christina Dirksen, Christopher P. Leamon
    Abstract:

    Folate receptor (FR) targeted small molecule drug conjugates (SMDC) have shown promising results in early stage clinical trials with Vintafolide and EC1456. In our effort to develop FR targeted SMDCs with varying mechanisms of action, we have now built a folate conjugate of a DNA crosslinking agent based on a novel DNA-alkylating moiety. This agent was found to be extremely potent with an in vitro IC50 ∼ 100 x lower than any other folate SMDC we have created to date. Treatment of nude mice bearing FR positive human xenografts led to cures in 100% of the mice at very low doses (> 500 nmol/kg) and a convenient once a week schedule. The observed activity was not accompanied by any noticeable weight loss (up to 20 weeks post end of dosing) or major organ tissue degeneration. In contrast, no significant anti-tumor activity (0% CR’s) was observed in treated animals that were co-dosed with an excess of a benign folate ligand, thus demonstrating its target-specific activity. Complete responses were also observed in other FR positive drug resistant (paclitaxel and cisplatin) models. Taken together, these studies demonstrated that this SMDC with a distinct DNA reacting mechanism has significant anti-tumor growth activity and tolerability, thus lending support to future clinical development of this novel FR-targeted agent. Citation Format: Joseph A. Reddy, Melissa Nelson, Theresa Johnson, Christina Dirksen, Marilynn Vetzel, Spencer Hahn, LongWu Qi, Iontcho Vlahov, Christopher Leamon. Pre-clinical studies of a highly potent folate receptor targeted DNA crosslinking agent. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3754.

Melissa Nelson - One of the best experts on this subject based on the ideXlab platform.

  • Pre-clinical studies of EC2629, a highly potent folate- receptor-targeted DNA crosslinking agent
    Scientific Reports, 2020
    Co-Authors: Joseph A. Reddy, Marilynn Vetzel, Melissa Nelson, Hari Krishna Santhapuram, Christina Dircksen, Theresa Johnson, Vicky Cross, Elaine Westrick, Spencer Hahn, Garth Parham
    Abstract:

    Folate receptor (FR)-targeted small molecule drug conjugates (SMDCs) have shown promising results in early stage clinical trials with microtubule destabilizing agents, such as Vintafolide and EC1456. In our effort to develop FR-targeted SMDCs with varying mechanisms of action, we synthesized EC2629, a folate conjugate of a DNA crosslinking agent based on a novel DNA-alkylating moiety. This agent was found to be extremely potent with an in vitro IC50 ~ 100× lower than folate SMDCs constructed with various microtubule inhibitors. EC2629 treatment of nude mice bearing FR-positive KB human xenografts led to cures in 100% of the test animals with very low dose levels (300 nmol/kg) following a convenient once a week schedule. The observed activity was not accompanied by any noticeable weight loss (up to 20 weeks post end of dosing). Complete responses were also observed against FR-positive paclitaxel (KB-PR) and cisplatin (KB-CR) resistant models. When evaluated against FR-positive patient derived xenograft (PDX) models of ovarian (ST070), endometrial (ST040) and triple negative breast cancers (ST502, ST738), EC2629 showed significantly greater anti-tumor activity compared to their corresponding standard of care treatments. Taken together, these studies thus demonstrated that EC2629, with its distinct DNA reacting mechanism, may be useful in treating FR-positive tumors, including those that are classified as drug resistant.

  • Pre-clinical evaluation of EC1456, a folate-tubulysin anti-cancer therapeutic
    Scientific Reports, 2018
    Co-Authors: Joseph A. Reddy, Alicia Bloomfield, Ryan Dorton, Marilynn Vetzel, Melissa Nelson, Iontcho R. Vlahov, Christina Dircksen, Paul Kleindl, Hari Santhapuram, Christopher P. Leamon
    Abstract:

    EC1456 is a folate-tubulysin conjugate constructed with an all-D enantiomeric spacer/linker configuration. When tested against folate receptor (FR)-positive cells, EC1456 demonstrated dose-responsive activity with an approximate 1000-fold level of specificity. Treatment of nude mice bearing FR-positive human xenografts (as large as 800 mm^3) with non-toxic doses of EC1456 led to cures in 100% of the mice. Combinations of low dose EC1456 with standard of care agents such as platins, taxanes, topotecan and bevacizumab, safely and significantly augmented the growth inhibitory effects of these commonly used agents. When tested against FR-positive human tumor xenograft models having confirmed resistance to a folate-vinca alkaloid (Vintafolide), cisplatin or paclitaxel, EC1456 was found to generate partial to curative responses. Taken together, these studies demonstrate that EC1456 has significant anti-proliferative activity against FR-positive tumors, including models which were anticancer drug resistant, thereby justifying a Phase 1 trial of this agent for the treatment of advanced human cancers.

  • Abstract 2133: Pre-clinical studies of EC2629, a highly potent FR targeted DNA crosslinking agent
    Experimental and Molecular Therapeutics, 2017
    Co-Authors: Joseph A. Reddy, Marilynn Vetzel, Melissa Nelson, Iontcho R. Vlahov, Christina Dircksen, Theresa Johnson, Spencer Hahn, Christopher P. Leamon
    Abstract:

    Folate receptor (FR) targeted small molecule drug conjugates (SMDCs) have shown promising results in early stage clinical trials with Vintafolide and EC1456. In our effort to develop FR targeted SMDCs with varying mechanisms of action, we have now built EC2629, a folate conjugate of a DNA crosslinking agent based on a novel DNA-alkylating moiety . This agent was found to be extremely potent with an in vitro IC50 ~ 100 x lower than any other folate SMDC we have created to date. Treatment of nude mice bearing FR positive human xenografts led to cures in 100% of the mice at very low doses (300 nmol/kg) using a convenient once a week schedule. The observed activity was not accompanied by any noticeable weight loss (up to 20 weeks post end of dosing) or major organ tissue degeneration. Complete responses were also observed in other FR-positive drug resistant (paclitaxel and cisplatin) models. When evaluated against FR-positive PDX models of ovarian, endometrial and triple negative breast (TNBC) cancers, EC2629 showed significantly greater anti-tumor activity than EC1456 or standard of care (SOC) treatments. Taken together, these studies demonstrated that EC2629 with a distinct DNA reacting mechanism has significant anti-tumor growth activity in numerous models, including those which were drug resistant, thus lending support to our planned clinical development of this novel FR-targeted agent. Citation Format: Joseph A. Reddy, Melissa Nelson, Christina Dircksen, Theresa Johnson, Marilynn Vetzel, Spencer Hahn, Longwu Qi, Iontcho Vlahov, Christopher Leamon. Pre-clinical studies of EC2629, a highly potent FR targeted DNA crosslinking agent [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2133. doi:10.1158/1538-7445.AM2017-2133

  • high levels of expression of p glycoprotein multidrug resistance protein result in resistance to Vintafolide
    Molecular Cancer Therapeutics, 2016
    Co-Authors: Amy D. Guertin, Joseph A. Reddy, Alicia Bloomfield, Ryan Dorton, Brian B. Haines, Marlene C. Hinton, Jennifer Oneil, Alexander Stoeck, Razvan Cristescu, Melissa Nelson
    Abstract:

    Targeting surface receptors overexpressed on cancer cells is one way to specifically treat cancer versus normal cells. Vintafolide (EC145), which consists of folate linked to a cytotoxic small molecule, desacetylvinblastine hydrazide (DAVLBH), takes advantage of the overexpression of folate receptor (FR) on cancer cells. Once bound to FR, Vintafolide enters the cell by endocytosis, and the reducing environment of the endosome cleaves the linker, releasing DAVLBH to destabilize microtubules. Vintafolide has shown efficacy and improved tolerability compared with DAVLBH in FR-positive preclinical models. As the first FR-targeting drug to reach the clinic, Vintafolide has achieved favorable responses in phase II clinical trials in FR-positive ovarian and lung cancer. However, some FR-positive patients in these clinical trials do not respond to Vintafolide. We sought to identify potential biomarkers of resistance to aid in the future development of this and other FR-targeting drugs. Here, we confirm that high P-glycoprotein (P-gp) expression was the strongest predictor of resistance to DAVLBH in a panel of 359 cancer cell lines. Furthermore, targeted delivery of DAVLBH via the FR, as in Vintafolide, fails to overcome P-gp-mediated efflux of DAVLBH in both in vitro and in vivo preclinical models. Therefore, we suggest that patients whose tumors express high levels of P-gp be excluded from future clinical trials for Vintafolide as well as other FR-targeted therapeutics bearing a P-gp substrate. Mol Cancer Ther; 15(8); 1998-2008. ©2016 AACR.

  • Abstract 3754: Pre-clinical studies of a highly potent folate receptor targeted DNA crosslinking agent
    Experimental and Molecular Therapeutics, 2016
    Co-Authors: Joseph A. Reddy, Marilynn Vetzel, Melissa Nelson, Iontcho R. Vlahov, Theresa Johnson, Spencer Hahn, Christina Dirksen, Christopher P. Leamon
    Abstract:

    Folate receptor (FR) targeted small molecule drug conjugates (SMDC) have shown promising results in early stage clinical trials with Vintafolide and EC1456. In our effort to develop FR targeted SMDCs with varying mechanisms of action, we have now built a folate conjugate of a DNA crosslinking agent based on a novel DNA-alkylating moiety. This agent was found to be extremely potent with an in vitro IC50 ∼ 100 x lower than any other folate SMDC we have created to date. Treatment of nude mice bearing FR positive human xenografts led to cures in 100% of the mice at very low doses (> 500 nmol/kg) and a convenient once a week schedule. The observed activity was not accompanied by any noticeable weight loss (up to 20 weeks post end of dosing) or major organ tissue degeneration. In contrast, no significant anti-tumor activity (0% CR’s) was observed in treated animals that were co-dosed with an excess of a benign folate ligand, thus demonstrating its target-specific activity. Complete responses were also observed in other FR positive drug resistant (paclitaxel and cisplatin) models. Taken together, these studies demonstrated that this SMDC with a distinct DNA reacting mechanism has significant anti-tumor growth activity and tolerability, thus lending support to future clinical development of this novel FR-targeted agent. Citation Format: Joseph A. Reddy, Melissa Nelson, Theresa Johnson, Christina Dirksen, Marilynn Vetzel, Spencer Hahn, LongWu Qi, Iontcho Vlahov, Christopher Leamon. Pre-clinical studies of a highly potent folate receptor targeted DNA crosslinking agent. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3754.

Marilynn Vetzel - One of the best experts on this subject based on the ideXlab platform.

  • Pre-clinical studies of EC2629, a highly potent folate- receptor-targeted DNA crosslinking agent
    Scientific Reports, 2020
    Co-Authors: Joseph A. Reddy, Marilynn Vetzel, Melissa Nelson, Hari Krishna Santhapuram, Christina Dircksen, Theresa Johnson, Vicky Cross, Elaine Westrick, Spencer Hahn, Garth Parham
    Abstract:

    Folate receptor (FR)-targeted small molecule drug conjugates (SMDCs) have shown promising results in early stage clinical trials with microtubule destabilizing agents, such as Vintafolide and EC1456. In our effort to develop FR-targeted SMDCs with varying mechanisms of action, we synthesized EC2629, a folate conjugate of a DNA crosslinking agent based on a novel DNA-alkylating moiety. This agent was found to be extremely potent with an in vitro IC50 ~ 100× lower than folate SMDCs constructed with various microtubule inhibitors. EC2629 treatment of nude mice bearing FR-positive KB human xenografts led to cures in 100% of the test animals with very low dose levels (300 nmol/kg) following a convenient once a week schedule. The observed activity was not accompanied by any noticeable weight loss (up to 20 weeks post end of dosing). Complete responses were also observed against FR-positive paclitaxel (KB-PR) and cisplatin (KB-CR) resistant models. When evaluated against FR-positive patient derived xenograft (PDX) models of ovarian (ST070), endometrial (ST040) and triple negative breast cancers (ST502, ST738), EC2629 showed significantly greater anti-tumor activity compared to their corresponding standard of care treatments. Taken together, these studies thus demonstrated that EC2629, with its distinct DNA reacting mechanism, may be useful in treating FR-positive tumors, including those that are classified as drug resistant.

  • Pre-clinical evaluation of EC1456, a folate-tubulysin anti-cancer therapeutic
    Scientific Reports, 2018
    Co-Authors: Joseph A. Reddy, Alicia Bloomfield, Ryan Dorton, Marilynn Vetzel, Melissa Nelson, Iontcho R. Vlahov, Christina Dircksen, Paul Kleindl, Hari Santhapuram, Christopher P. Leamon
    Abstract:

    EC1456 is a folate-tubulysin conjugate constructed with an all-D enantiomeric spacer/linker configuration. When tested against folate receptor (FR)-positive cells, EC1456 demonstrated dose-responsive activity with an approximate 1000-fold level of specificity. Treatment of nude mice bearing FR-positive human xenografts (as large as 800 mm^3) with non-toxic doses of EC1456 led to cures in 100% of the mice. Combinations of low dose EC1456 with standard of care agents such as platins, taxanes, topotecan and bevacizumab, safely and significantly augmented the growth inhibitory effects of these commonly used agents. When tested against FR-positive human tumor xenograft models having confirmed resistance to a folate-vinca alkaloid (Vintafolide), cisplatin or paclitaxel, EC1456 was found to generate partial to curative responses. Taken together, these studies demonstrate that EC1456 has significant anti-proliferative activity against FR-positive tumors, including models which were anticancer drug resistant, thereby justifying a Phase 1 trial of this agent for the treatment of advanced human cancers.

  • Abstract 2133: Pre-clinical studies of EC2629, a highly potent FR targeted DNA crosslinking agent
    Experimental and Molecular Therapeutics, 2017
    Co-Authors: Joseph A. Reddy, Marilynn Vetzel, Melissa Nelson, Iontcho R. Vlahov, Christina Dircksen, Theresa Johnson, Spencer Hahn, Christopher P. Leamon
    Abstract:

    Folate receptor (FR) targeted small molecule drug conjugates (SMDCs) have shown promising results in early stage clinical trials with Vintafolide and EC1456. In our effort to develop FR targeted SMDCs with varying mechanisms of action, we have now built EC2629, a folate conjugate of a DNA crosslinking agent based on a novel DNA-alkylating moiety . This agent was found to be extremely potent with an in vitro IC50 ~ 100 x lower than any other folate SMDC we have created to date. Treatment of nude mice bearing FR positive human xenografts led to cures in 100% of the mice at very low doses (300 nmol/kg) using a convenient once a week schedule. The observed activity was not accompanied by any noticeable weight loss (up to 20 weeks post end of dosing) or major organ tissue degeneration. Complete responses were also observed in other FR-positive drug resistant (paclitaxel and cisplatin) models. When evaluated against FR-positive PDX models of ovarian, endometrial and triple negative breast (TNBC) cancers, EC2629 showed significantly greater anti-tumor activity than EC1456 or standard of care (SOC) treatments. Taken together, these studies demonstrated that EC2629 with a distinct DNA reacting mechanism has significant anti-tumor growth activity in numerous models, including those which were drug resistant, thus lending support to our planned clinical development of this novel FR-targeted agent. Citation Format: Joseph A. Reddy, Melissa Nelson, Christina Dircksen, Theresa Johnson, Marilynn Vetzel, Spencer Hahn, Longwu Qi, Iontcho Vlahov, Christopher Leamon. Pre-clinical studies of EC2629, a highly potent FR targeted DNA crosslinking agent [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2133. doi:10.1158/1538-7445.AM2017-2133

  • Abstract 3754: Pre-clinical studies of a highly potent folate receptor targeted DNA crosslinking agent
    Experimental and Molecular Therapeutics, 2016
    Co-Authors: Joseph A. Reddy, Marilynn Vetzel, Melissa Nelson, Iontcho R. Vlahov, Theresa Johnson, Spencer Hahn, Christina Dirksen, Christopher P. Leamon
    Abstract:

    Folate receptor (FR) targeted small molecule drug conjugates (SMDC) have shown promising results in early stage clinical trials with Vintafolide and EC1456. In our effort to develop FR targeted SMDCs with varying mechanisms of action, we have now built a folate conjugate of a DNA crosslinking agent based on a novel DNA-alkylating moiety. This agent was found to be extremely potent with an in vitro IC50 ∼ 100 x lower than any other folate SMDC we have created to date. Treatment of nude mice bearing FR positive human xenografts led to cures in 100% of the mice at very low doses (> 500 nmol/kg) and a convenient once a week schedule. The observed activity was not accompanied by any noticeable weight loss (up to 20 weeks post end of dosing) or major organ tissue degeneration. In contrast, no significant anti-tumor activity (0% CR’s) was observed in treated animals that were co-dosed with an excess of a benign folate ligand, thus demonstrating its target-specific activity. Complete responses were also observed in other FR positive drug resistant (paclitaxel and cisplatin) models. Taken together, these studies demonstrated that this SMDC with a distinct DNA reacting mechanism has significant anti-tumor growth activity and tolerability, thus lending support to future clinical development of this novel FR-targeted agent. Citation Format: Joseph A. Reddy, Melissa Nelson, Theresa Johnson, Christina Dirksen, Marilynn Vetzel, Spencer Hahn, LongWu Qi, Iontcho Vlahov, Christopher Leamon. Pre-clinical studies of a highly potent folate receptor targeted DNA crosslinking agent. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3754.

  • Abstract 4488: Folate receptor targeted therapy using small molecule drug conjugates constructed with high affinity antifolate ligands
    Experimental and Molecular Therapeutics, 2015
    Co-Authors: Christopher P. Leamon, Joseph A. Reddy, Marilynn Vetzel, Melissa Nelson, Iontcho R. Vlahov, Fei You, Paul J. Kleindl, Patrick J. Klein, Hanna F. Klein, Larry H Matherly
    Abstract:

    Folate receptor (FR)-targeted small molecule drug conjugates (SMDC) have shown promising clinical results. To date, all related SMDCs have been constructed with folic acid. Whereas folic acid displays very high affinity for the FR (kd ∼ 0.1 nM), antifolates with similar high binding affinity and specificity have also been reported. This knowledge prompted our investigation towards substituting the folic acid targeting moiety in our SMDCs with high affinity antifolates, such as CB3717 (a thymidylate synthase inhibitor), and the glycinamide ribonucleotide formyltransferase (GARFTase) inhibitors, AG94 and AG147, thereby testing the hypothesis that greater antitumor activity should result from the combination of inhibitors. Using mice bearing FR-positive human tumor xenografts, we observed curative activity with a CB3717-based vinca alkaloid SMDC under conditions where no cures resulted with Vintafolide (EC145) treatment. Similarly, tubulysin SMDCs constructed with AG94 and AG147 were found to produce curative activity using a dosing regimen where a folic acid-tubulysin conjugate did not. Of note, treatment of mice with simple co-mixtures of the antifolates and untargeted drugs was found to be ineffective, thereby confirming the need for linking the two moieties together to produce maximal activity. Taken together, these studies demonstrate that high affinity antifolates can be used in an SMDC format serving as both a high affinity targeting ligand and as a second drug having different, and perhaps a complementary mechanism of action to yield greater antitumor activity. Citation Format: Christopher P. Leamon, Joseph A. Reddy, Iontcho R. Vlahov, Fei You, Hanna F. Klein, Paul J. Kleindl, Melissa Nelson, Marilynn Vetzel, Patrick J. Klein, Larry H. Matherly, Aleem Gangjee. Folate receptor targeted therapy using small molecule drug conjugates constructed with high affinity antifolate ligands. [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 4488. doi:10.1158/1538-7445.AM2015-4488

Binh Nguyen - One of the best experts on this subject based on the ideXlab platform.

  • Adverse Event Profile by Folate Receptor Status for Vintafolide and Pegylated Liposomal Doxorubicin in Combination, Versus Pegylated Liposomal Doxorubicin Alone, in Platinum-Resistant Ovarian Cancer: Exploratory Analysis of the Phase II PRECEDENT Tri
    International journal of gynecological cancer : official journal of the International Gynecological Cancer Society, 2016
    Co-Authors: Thomas J. Herzog, Elzbieta Kutarska, James T. Symanowski, Binh Nguyen, Reshma A. Rangwala, Mariusz Bidzińsk, R. Wendel Naumann
    Abstract:

    Objective This exploratory analysis evaluated the incidence of adverse events (AEs) by folate receptor (FR) status in the randomized, multicenter, open-label PRECEDENT study in women with platinum-resistant ovarian cancer receiving pegylated liposomal doxorubicin (PLD) ± the small-molecule drug conjugate Vintafolide. Methods Women 18 years or older with platinum-resistant ovarian cancer were randomized 2:1 to Vintafolide (2.5 mg intravenously, 3 times per week, weeks 1 and 3, every 28 days) + PLD (50 mg/m2 intravenously, day 1, every 28 days) or PLD alone (same dose/schedule). The expression of functionally active FR was evaluated by single-photon emission computed tomography with etarfolatide. Patients were categorized according to FR positivity: patients with all target lesions positive for FR expression (FR 100%), patients with 1 or more but not all target lesions positive for FR expression (FR 10%–90%), and patients with all lesions negative for FR expression (FR 0%). Results Data on FR status were available for 94 patients: 38 were FR 100%, 36 were FR 10% to 90%, and 20 were FR 0%. Across all FR subgroups, the duration of treatment was longer, and the number of cycles was higher in combination-therapy arms than PLD-alone arms. Although the frequency of AEs was relatively consistent across subgroups, the FR 100% subgroup had a higher incidence of patients with at least 1 AE for combination therapy versus PLD alone. No surprising safety signals were shown according to FR status. The incidence of grade 3 or 4 treatment-emergent drug-related AEs was generally low across all FR subgroups and treatment arms. Conclusions This exploratory analysis suggests that FR status does not influence the AE profile of Vintafolide + PLD combination therapy or PLD alone in patients with platinum-resistant ovarian cancer. Future a priori analyses in larger populations are needed to confirm these findings.

  • Real-time identification of tumor lesions and response to Vintafolide treatment.
    Journal of Clinical Oncology, 2014
    Co-Authors: Wael A Harb, Binh Nguyen, Siu-long Yao, Robin Mogg
    Abstract:

    5533 Background: In treating cancer, companion diagnostics are most useful when they can identify patients who cannot benefit from treatment. However, existing tests suffer from inaccuracy due to d...

  • Imaging the Folate Receptor on Cancer Cells with 99mTc-Etarfolatide: Properties, Clinical Use, and Future Potential of Folate Receptor Imaging
    Journal of nuclear medicine : official publication Society of Nuclear Medicine, 2014
    Co-Authors: Alan H. Maurer, Binh Nguyen, Philippus Elsinga, Stefano Fanti, Wim J.g. Oyen, Wolfgang A. Weber
    Abstract:

    Folate receptor (FR) can be used as a therapeutic target because of its expression on different epithelial cancers, such as ovarian, non-small cell lung, endometrial, and breast cancer. Assessing FR expression in tumors may help to identify patients who can benefit from FR-targeted therapeutics, such as Vintafolide and farletuzumab. Different methods exist to detect FR expression. Tissue sampling has limited clinical utility, mainly because it requires an invasive procedure. (99m)Tc-etarfolatide, a (99m)Tc-labeled folate conjugate, is in late-phase trials in Europe and the United States. It allows noninvasive, whole-body imaging of the FR. This review focuses on this FR-imaging agent and how it may be used to direct FR-targeted therapy.

  • LBA40_PRTARGET: A RANDOMIZED, PHASE II TRIAL COMPARING Vintafolide VERSUS Vintafolide PLUS DOCETAXEL, VERSUS DOCETAXEL ALONE IN SECOND-LINE TREATMENT OF FOLATE-RECEPTOR-POSITIVE NON-SMALL CELL LUNG CANCER (NSCLC) PATIENTS
    Annals of Oncology, 2014
    Co-Authors: Nasser H. Hanna, James T. Symanowski, E. Juhasz, C. Cainap, O. Gladkov, R. Ramlau, O. Juan-vidal, Rohit Lal, W. Perez, Binh Nguyen
    Abstract:

    ABSTRACT Aim: The folate receptor (FR) is expressed in many epithelial cancers, including NSCLC, and may be a useful biomarker for therapy selection. Vintafolide, a folate-vinca alkaloid drug conjugate, is a FR-targeted drug. Its companion imaging agent, 99mTc-etarfolatide, enables non-invasive imaging of FR expression. The TARGET study (NCT01577654) assessed the benefit of FR-targeted therapy in 199 second-line NSCLC patients with all target lesions expressing FR [FR(100%)]. Methods: Patients were randomized 1:1:1 to Vintafolide, Vintafolide + docetaxel (DTX), or DTX alone. Vintafolide (2.5 mg) was administered on D1, 4, 8, and 11 and DTX (75 mg/m2) on D1 of a 3-week cycle. The primary endpoint was PFS; secondary endpoints included OS and ORR. The significance level of each PFS and OS analysis was one-sided alpha = 0.10 with no multiple testing adjustments. Results: See table. Vintafolide Vinta + DTX DTX All patients ORR Median PFS (months, 95% Cl) PFS HR (vs. DTX; 95% Cl)* 1-sided p-value Median OS (months, 95% Cl) OS HR (vs. DTX; 95% Cl)* 1-sided p-value N = 63 6% 1.6 (1.4; 3.2) 1.35 (0.92; 1.96) 0.9421 8.4 (5.6; 12.3) 1.05 (0.68; 1.61) 0.5818 N = 68 22% 4.2 (2.8; 5.4) 0.75 (0.52; 1.09) 0.0696 11.5 (7.3; 13.4) 0.88 (0.58; 1.36) 0.2874 N = 68 13% 3.3 (1.72; 4.2) - - 8.8 (5.4; 12.6) - - Adenocarcinoma patients ORR Median PFS (months, 95% Cl) PFS HR (vs. DTX; 95% Cl)* 1-sided p-value Median OS (months, 95% Cl) OR HR (vs. DTX; 95% Cl)* 1-sided p-value N = 41 5% 1.6 (1.4; 3.3) 1.40 (0.88; 2.24) 0.9247 8.4 (5.1; 12.5) 1.00 (0.59; 1.71 0.4957 N = 43 21% 4.2 (2.6; 5.4) 0.73 (0.46; 1.16) 0.0899 12.5 (8.1; - ) 0.70 (0.40; 1.22) 0.1018 N = 49 14% 3.0 (1.6; 4.2) - - 6.6 (4.8; 12.9) - - * Unstratified Cox model. With the pre-specified stratified analysis adjusting for baseline factors (time since last chemotherapy, best response and stage), the OS HR for Vintafolide + DTX vs. DTX were 0.75 (1-sided p = 0.1066) for all patients, and 0.51 (1-sided p = 0.0147) for the predefined adenocarcinoma patient subgroup. Conclusions: Vintafolide + DTX showed clinically meaningful improvement across all efficacy endpoints (ORR, PFS and OS) over single-agent DTX, with the largest benefit observed in the adenocarcinoma subgroup. Disclosure: J. Symanowski: Other substantive relationships: Consultant for Endocyte, Inc.; W. Perez: Other substantive relationships: Employee of Endocyte, Inc.; W. Harb: Corporate-sponsored research: Endocyte sponsored participation in EC1456 study. All other authors have declared no conflicts of interest.

  • Patient selection and targeted treatment in the management of platinum-resistant ovarian cancer.
    Pharmacogenomics and personalized medicine, 2013
    Co-Authors: Christopher P. Leamon, Chandra D. Lovejoy, Binh Nguyen
    Abstract:

    Ovarian cancer (OC) has the highest mortality rate of any gynecologic cancer, and patients generally have a poor prognosis due to high chemotherapy resistance and late stage disease diagnosis. Platinum-resistant OC can be treated with cytotoxic chemotherapy such as paclitaxel, topotecan, pegylated liposomal doxorubicin, and gemcitabine, but many patients eventually relapse upon treatment. Fortunately, there are currently a number of targeted therapies in development for these patients who have shown promising results in recent clinical trials. These treatments often target the vascular endothelial growth factor pathway (eg, bevacizumab and aflibercept), DNA repair mechanisms (eg, iniparib and olaparib), or they are directed against folate related pathways (eg, pemetrexed, farletuzumab, and Vintafolide). As many targeted therapies are only effective in a subset of patients, there is an increasing need for the identification of response predictive biomarkers. Selecting the right patients through biomarker screening will help tailor therapy to patients and decrease superfluous treatment to those who are biomarker negative; this approach should lead to improved clinical results and decreased toxicities. In this review the current targeted therapies used for treating platinum-resistant OC are discussed. Furthermore, use of prognostic and response predictive biomarkers to define OC patient populations that may benefit from specific targeted therapies is also highlighted.