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Madeleine Duvic - One of the best experts on this subject based on the ideXlab platform.
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oral Bexarotene for post transplant cutaneous t cell lymphoma
Dermatologic Therapy, 2017Co-Authors: Simo Huang, Daniel J Lewis, Madeleine DuvicAbstract:Organ transplant recipients receiving immunosuppression have an increased risk of developing post-transplant lymphoproliferative diseases (PTLDs). Traditionally, PTLDs refer to Epstein-Barr virus (EBV)-induced B-cell lymphoma. However, post-transplant T-cell lymphoma may also occur and tends to have a poorer response to reduced immunosuppressive therapy. As such, additional therapy is often needed for post-transplant T-cell lymphoma, including post-transplant cutaneous T-cell lymphoma (PT-CTCL). We present only the third case of PT-CTCL occurring after liver transplantation. The patient was diagnosed with stage IB mycosis fungoides (MF). His lesions were refractory to multiple skin-directed therapies, and so he was given oral Bexarotene 150 mg daily and his oral tacrolimus dose was decreased to 2 mg daily. Remarkably, his MF patches have demonstrated a complete response to oral Bexarotene 75 mg daily without recurrence over 11 years of follow-up. He developed hypertriglyceridemia with Bexarotene 150 mg, so his dose was decreased to 75 mg, without loss of response. Our report is the second to describe PT-CTCL demonstrating a long-term complete response to oral Bexarotene. Given its anti-carcinogenic properties and favorable toxicity profile, oral Bexarotene represents an appealing treatment option for PT-CTCL refractory to skin-directed therapies.
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Results from a Phase I/II Open-Label, Dose-Finding Study of Pralatrexate and Oral Bexarotene in Patients with Relapsed/Refractory Cutaneous T-cell Lymphoma.
Clinical cancer research : an official journal of the American Association for Cancer Research, 2017Co-Authors: Madeleine Duvic, Pier Luigi Zinzani, Youn H. Kim, Steven M. HorwitzAbstract:Purpose: Pralatrexate is a folic acid analogue metabolic inhibitor similar to methotrexate, which has shown tolerability and efficacy with an overall response rate of 45% in a phase I dose deescalation study of patients with relapsed/refractory cutaneous T-cell lymphoma (CTCL).Experimental Design: The object of this phase I/II open-label, multicenter clinical trial was to determine the MTD and recommended dose of pralatrexate plus oral Bexarotene in 34 patients with relapsed/refractory CTCL who had failed prior systemic therapies. Pralatrexate was administered by intravenous push at 15 mg/m2 given weekly 3 weeks out of 4 weeks with daily oral Bexarotene (150 or 300 mg/m2), levothyroxine, atorvastatin, folate, and with B12 every 2 months.Results: At the MTD of 15 mg/m2 Bexarotene and 15 mg/m2 pralatrexate, the response rate was 60% [4 complete responses (CR), 14 partial responses (PR)], the maximum observed response duration was 28.9+ months, and duration of response for 4 CRs ranged from 9.0 to 28.3 months. The median progression-free survival was 12.8 months (0.5-29.9). Mucositis was the most common adverse event.Conclusions: The combination of pralatrexate (15 mg/m2) and oral Bexarotene (150 mg/m2) is active with high response rates and minimal toxicity for cutaneous T-cell lymphomas. Clin Cancer Res; 23(14); 3552-6. ©2017 AACR.
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pralatrexate alone or in combination with Bexarotene long term tolerability in relapsed refractory mycosis fungoides
Clinical Lymphoma Myeloma & Leukemia, 2014Co-Authors: Rakhshandra Talpur, Andrew Thompson, Pamela Gangar, Madeleine DuvicAbstract:Abstract Background This study aimed to assess the long-term tolerability of pralatrexate alone or in combination with oral Bexarotene for relapsed or refractory mycosis fungoides (MF). Patients and Methods Patients with MF in this report were participants in 1 of 2 multicenter trials. During the dose-ranging phase I/II study, participants were treated with pralatrexate alone for 3 of 4 weeks. During a second phase I/II dose-ranging combination trial, participants were treated with pralatrexate at 15 mg/m 2 /wk for 3 of 4 weeks combined with 150 to 300 mg/m 2 of daily oral Bexarotene. Results Twenty-six patients were enrolled at our center, including 12 receiving pralatrexate and 14 receiving pralatrexate plus Bexarotene. Four of 12 patients (33%) treated with pralatrexate alone responded. Of 14 patients treated with Bexarotene plus pralatrexate, 7 (50%) responded. Ten participants, with a median age of 71 years (range, 41-82 years), received more than 9 cycles of pralatrexate, including 3 receiving pralatrexate and 7 receiving combination therapy. Median time to response was 15.75 weeks (range, 4-24 weeks), and the median duration of response was 26.75 weeks (range, 8.5-49.5 weeks). The most common adverse event (AE) was mucositis in 8 (80%) patients. Other AEs of any grade included arthralgias (n = 1), headache (n = 1), neutropenia (n = 5), and skin necrosis (n = 2). Two patients initially had lower leg tumors that responded to therapy, leaving residual chronic leg ulcers. Conclusion Pralatrexate alone or in combination with low-dose oral Bexarotene is well tolerated and capable of providing long-term responses in patients of advanced age with advanced-stage MF.
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panobinostat activity in both Bexarotene exposed and naive patients with refractory cutaneous t cell lymphoma results of a phase ii trial
European Journal of Cancer, 2013Co-Authors: Madeleine Duvic, Chalid Assaf, Reinhard Dummer, Jurgen C Becker, N Poulalhon, Pablo Luis Ortiz Romero, Maria Grazia Bernengo, Celeste Lebbe, Margaret Squier, Denise WilliamsAbstract:Abstract Background Panobinostat is a potent, oral pan-deacetylase inhibitor (pan-DACi) that increases the acetylation of proteins involved in multiple oncogenic pathways. Here, panobinostat is studied in Bexarotene-exposed and -naive patients with refractory cutaneous T-cell lymphoma (CTCL). Patients and methods Patients with CTCL subtypes mycosis fungoides and Sezary syndrome who received ⩾2 prior systemic therapy regimens received panobinostat (20 mg) three times every week. The primary objective was overall response rate (ORR) as determined by a combined evaluation of skin disease and involvement of lymph node and viscera. Disease progression was defined as an unconfirmed, ⩾25% increase in modified Severity Weighted Assessment Tool (mSWAT) compared with nadir. Results Seventy-nine Bexarotene-exposed and 60 Bexarotene-naive patients were enrolled. Reductions in baseline mSWAT scores were observed in 103 patients (74.1%). The ORR was 17.3% in all patients in the primary analysis (15.2% and 20.0% in the Bexarotene-exposed and -naive groups, respectively). The median progression-free survival was 4.2 and 3.7 months in the Bexarotene-exposed and -naive groups, respectively. The median duration of response was 5.6 months in the Bexarotene-exposed patients and was not reached at data cutoff in the Bexarotene-naive patients. Additional responses were observed when less-stringent progression criteria were used. The most common adverse events were thrombocytopenia, diarrhoea, fatigue and nausea. Thrombocytopenia and neutropenia were the only grade 3/4 adverse events in >5% of patients and were manageable. Conclusion Despite a very conservative definition of disease progression, panobinostat demonstrated activity with a manageable safety profile in Bexarotene-exposed and -naive CTCL patients. ClinicalTrials.gov Identifier: NCT00425555 .
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phase i ii randomized bilateral half head comparison of topical Bexarotene 1 gel for alopecia areata
Journal of The American Academy of Dermatology, 2009Co-Authors: Rakhshandra Talpur, Victor Stevens, Roland L Bassett, Madeleine DuvicAbstract:Background Alopecia areata, hair loss caused by perifollicular T-cell infiltrates, is refractory to therapy. Bexarotene, a retinoid X receptor is a selective retinoid, induces T-cell apoptosis. Objective We sought to determine the safety, including the dose-limiting toxicities with adverse events, and efficacy, ie, response rate, of Bexarotene in alopecia areata. Methods We conducted a phase I/II randomized, half-head trial of 1% Bexarotene gel applied twice daily for 6 months. Results In all, 42 patients (11 male and 31 female) with alopecia totalis (n = 3), alopecia universalis (n = 5), or alopecia areata (n = 34) applied 1% Bexarotene gel for 24 weeks. Five of 42 (12%) had 50% or more partial hair regrowth on the treated side, and 6 of 42 (14%) on both sides including 3 complete responders. In all, 31 patients had mild irritation; 4 had grade-3 irritation. Limitations This design cannot differentiate between drug-induced and spontaneous regrowth. Conclusion Topical Bexarotene 1% application is well tolerated and possibly effective. A randomized placebo-controlled trial should be conducted.
James R Rigas - One of the best experts on this subject based on the ideXlab platform.
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a proof of principle clinical trial of Bexarotene in patients with non small cell lung cancer
Clinical Cancer Research, 2007Co-Authors: Konstantin H Dragnev, Jeffrey W Petty, Sumit J Shah, Lionel D Lewis, Candice C Black, Vincent A Memoli, William C Nugent, Thomas Hermann, Andres Negrovilar, James R RigasAbstract:Purpose: Bexarotene is a rexinoid (selective retinoid X receptor agonist) that affects proliferation, differentiation, and apoptosis in preclinical studies. The relationship between Bexarotene levels and biomarker changes in tumor tissues has not been previously studied. Experimental Design: BEAS-2B human bronchial epithelial (HBE) cells, retinoid-resistant BEAS-2B-R1 cells, A427, H226, and H358 lung cancer cells were treated with Bexarotene. Proliferation and biomarker expression were assessed. In a proof-of-principle clinical trial, Bexarotene tumor tissue levels and intratumoral pharmacodynamic effects were assessed in patients with stages I to II non–small cell lung cancer. Bexarotene (300 mg/m 2 /day) was administered p.o. for 7 to 9 days before resection. Results: Bexarotene-induced dosage-dependent repression of growth, cyclin D1, cyclin D3, total epidermal growth factor receptor (EGFR), and phospho-EGFR expression in BEAS-2B, BEAS-2B-R1, A427, and H358, but not H226 cells. Twelve patients were enrolled, and 10 were evaluable. Bexarotene treatment was well tolerated. There was nonlinear correlation between plasma and tumor Bexarotene concentrations ( r 2 = 0.77). Biomarker changes in tumors were observed: repression of cyclin D1, total EGFR and proliferation in one case; repression of cyclin D3, total and phospho-EGFR in another. The cases with multiple biomarker changes had high tumor Bexarotene (107-159 ng/g). A single biomarker change was detected in one case with low tumor Bexarotene. Conclusion: Bexarotene represses proliferation and biomarker expression in responsive, but not resistant HBE and lung cancer cells. Similar biomarker changes occur in lung tumors when therapeutic intratumoral Bexarotene levels are achieved. This proof-of-principle trial approach is useful to uncover pharmacodynamic mechanisms in vivo and relate these to intratumoral pharmacokinetic effects.
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Bexarotene and erlotinib for aerodigestive tract cancer
Journal of Clinical Oncology, 2005Co-Authors: Konstantin H Dragnev, Jeffrey W Petty, Sumit J Shah, Vincent A Memoli, James R Rigas, Adrian Biddle, Neil Desai, Ethan DmitrovskyAbstract:Purpose The epidermal growth factor receptor (EGFR) and cyclin D1 are overexpressed in lung carcinogenesis. The rexinoid, Bexarotene, represses cyclin D1 and EGFR expression in vitro. It was hypothesized that combining Bexarotene with the EGFR inhibitor, erlotinib, would augment clinical activity. Patients and Methods In vitro studies and a phase I clinical trial were performed. Twenty-four patients with advanced aerodigestive tract cancers were enrolled; 79% had non–small-cell lung cancer (NSCLC). The primary objective was to determine the maximum-tolerated dose. Clinical activity was a secondary objective. Results Combining erlotinib with Bexarotene enhanced growth suppression in vitro compared with each single-agent treatment. This cooperatively repressed cyclin D1 expression. Clinically, the most frequent toxicities were mild hypertriglyceridemia and skin rash. Two serious treatment-related adverse events occurred (creatine phosphokinase elevation attributed to antilipid therapy and a case of generali...
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emerging role of rexinoids in non small cell lung cancer focus on Bexarotene
Oncologist, 2005Co-Authors: James R Rigas, Konstantin H DragnevAbstract:Although the introduction of third-generation antineoplastic agents in the treatment of non-small cell lung cancer has led to modest improvements in overall patient survival, lung cancer continues to be the leading cause of cancer-related death worldwide, and improved therapies are needed. Retinoids play a critical role in the regulation of cell division, growth, differentiation, and proliferation, and they represent an exciting new avenue for targeted therapy. Several synthetic retinoids that bind to retinoic acid receptors are currently being investigated in a variety of tumor types. However, many of these agents have been associated with cheilitis, skin reactions, severe headache, and hypertriglyceridemia. Synthetic agents that bind specifically to retinoid X receptors are called rexinoids. Bexarotene (Targretin ® ; Ligand Pharmaceuticals; San Diego, CA; http://www.ligand.com) is a novel, multitargeted synthetic rexinoid that is currently being investigated in the treatment of non-small cell lung cancer. Phase I and II studies have demonstrated that Bexarotene is safe and well tolerated in this patient population either alone or in combination with chemotherapeutic agents. Patients treated with Bexarotene experience manageable adverse events at reduced levels compared with retinoic acid receptor-specific retinoids. Bexarotene in combination with chemotherapeutic agents has demonstrated an encouraging median survival for patients with advanced non-small cell lung cancer compared with historical results with combination chemotherapy alone. Two phase III trials are currently under way to fully characterize the role of Bexarotene in the treatment of this disease. The purpose of this review is to explore the rationale for rexinoids in the treatment of malignancies and to discuss the clinical profile of Bexarotene in the treatment of non-small cell lung cancer. The Oncologist 2005;10:22-33
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multi institutional phase i ii trial of oral Bexarotene in combination with cisplatin and vinorelbine in previously untreated patients with advanced non small cell lung cancer
Journal of Clinical Oncology, 2001Co-Authors: Fadlo R Khuri, James R Rigas, Robert A Figlin, Richard J Gralla, Dong M Shin, Reginald F Munden, Nikolaus Fox, Mi Ra Huyghe, Yin Kean, Steven D ReichAbstract:PURPOSE: Bexarotene (Targretin; Ligand Pharmaceuticals, Inc, San Diego, CA) is a retinoid-X-receptor (RXR)-selective retinoid with preclinical antitumor activity in squamous cell cancers. In this phase I/II trial, we combined Bexarotene with cisplatin and vinorelbine in the treatment of patients with non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Forty-three patients who had stage IIIB NSCLC with pleural effusion or stage IV NSCLC and had received no prior therapy received Bexarotene in combination with cisplatin (100 mg/m2) and vinorelbine (alternating doses of 30 mg/m2 and 15 mg/m2). In the phase I portion, the daily dose of Bexarotene was escalated in cohorts of three patients from 150 mg/m2 to 600 mg/m2, beginning 1 week before the start of the cisplatin-vinorelbine regimen. Once the maximum-tolerated dose (MTD) of Bexarotene was determined, the study entered the phase II portion. Response rate was the primary end point; median survival time and 1-year survival rate were secondary end point...
Konstantin H Dragnev - One of the best experts on this subject based on the ideXlab platform.
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a proof of principle clinical trial of Bexarotene in patients with non small cell lung cancer
Clinical Cancer Research, 2007Co-Authors: Konstantin H Dragnev, Jeffrey W Petty, Sumit J Shah, Lionel D Lewis, Candice C Black, Vincent A Memoli, William C Nugent, Thomas Hermann, Andres Negrovilar, James R RigasAbstract:Purpose: Bexarotene is a rexinoid (selective retinoid X receptor agonist) that affects proliferation, differentiation, and apoptosis in preclinical studies. The relationship between Bexarotene levels and biomarker changes in tumor tissues has not been previously studied. Experimental Design: BEAS-2B human bronchial epithelial (HBE) cells, retinoid-resistant BEAS-2B-R1 cells, A427, H226, and H358 lung cancer cells were treated with Bexarotene. Proliferation and biomarker expression were assessed. In a proof-of-principle clinical trial, Bexarotene tumor tissue levels and intratumoral pharmacodynamic effects were assessed in patients with stages I to II non–small cell lung cancer. Bexarotene (300 mg/m 2 /day) was administered p.o. for 7 to 9 days before resection. Results: Bexarotene-induced dosage-dependent repression of growth, cyclin D1, cyclin D3, total epidermal growth factor receptor (EGFR), and phospho-EGFR expression in BEAS-2B, BEAS-2B-R1, A427, and H358, but not H226 cells. Twelve patients were enrolled, and 10 were evaluable. Bexarotene treatment was well tolerated. There was nonlinear correlation between plasma and tumor Bexarotene concentrations ( r 2 = 0.77). Biomarker changes in tumors were observed: repression of cyclin D1, total EGFR and proliferation in one case; repression of cyclin D3, total and phospho-EGFR in another. The cases with multiple biomarker changes had high tumor Bexarotene (107-159 ng/g). A single biomarker change was detected in one case with low tumor Bexarotene. Conclusion: Bexarotene represses proliferation and biomarker expression in responsive, but not resistant HBE and lung cancer cells. Similar biomarker changes occur in lung tumors when therapeutic intratumoral Bexarotene levels are achieved. This proof-of-principle trial approach is useful to uncover pharmacodynamic mechanisms in vivo and relate these to intratumoral pharmacokinetic effects.
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Bexarotene and erlotinib for aerodigestive tract cancer
Journal of Clinical Oncology, 2005Co-Authors: Konstantin H Dragnev, Jeffrey W Petty, Sumit J Shah, Vincent A Memoli, James R Rigas, Adrian Biddle, Neil Desai, Ethan DmitrovskyAbstract:Purpose The epidermal growth factor receptor (EGFR) and cyclin D1 are overexpressed in lung carcinogenesis. The rexinoid, Bexarotene, represses cyclin D1 and EGFR expression in vitro. It was hypothesized that combining Bexarotene with the EGFR inhibitor, erlotinib, would augment clinical activity. Patients and Methods In vitro studies and a phase I clinical trial were performed. Twenty-four patients with advanced aerodigestive tract cancers were enrolled; 79% had non–small-cell lung cancer (NSCLC). The primary objective was to determine the maximum-tolerated dose. Clinical activity was a secondary objective. Results Combining erlotinib with Bexarotene enhanced growth suppression in vitro compared with each single-agent treatment. This cooperatively repressed cyclin D1 expression. Clinically, the most frequent toxicities were mild hypertriglyceridemia and skin rash. Two serious treatment-related adverse events occurred (creatine phosphokinase elevation attributed to antilipid therapy and a case of generali...
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emerging role of rexinoids in non small cell lung cancer focus on Bexarotene
Oncologist, 2005Co-Authors: James R Rigas, Konstantin H DragnevAbstract:Although the introduction of third-generation antineoplastic agents in the treatment of non-small cell lung cancer has led to modest improvements in overall patient survival, lung cancer continues to be the leading cause of cancer-related death worldwide, and improved therapies are needed. Retinoids play a critical role in the regulation of cell division, growth, differentiation, and proliferation, and they represent an exciting new avenue for targeted therapy. Several synthetic retinoids that bind to retinoic acid receptors are currently being investigated in a variety of tumor types. However, many of these agents have been associated with cheilitis, skin reactions, severe headache, and hypertriglyceridemia. Synthetic agents that bind specifically to retinoid X receptors are called rexinoids. Bexarotene (Targretin ® ; Ligand Pharmaceuticals; San Diego, CA; http://www.ligand.com) is a novel, multitargeted synthetic rexinoid that is currently being investigated in the treatment of non-small cell lung cancer. Phase I and II studies have demonstrated that Bexarotene is safe and well tolerated in this patient population either alone or in combination with chemotherapeutic agents. Patients treated with Bexarotene experience manageable adverse events at reduced levels compared with retinoic acid receptor-specific retinoids. Bexarotene in combination with chemotherapeutic agents has demonstrated an encouraging median survival for patients with advanced non-small cell lung cancer compared with historical results with combination chemotherapy alone. Two phase III trials are currently under way to fully characterize the role of Bexarotene in the treatment of this disease. The purpose of this review is to explore the rationale for rexinoids in the treatment of malignancies and to discuss the clinical profile of Bexarotene in the treatment of non-small cell lung cancer. The Oncologist 2005;10:22-33
Xiaochuan Sun - One of the best experts on this subject based on the ideXlab platform.
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the long non coding rna neat1 is an important mediator of the therapeutic effect of Bexarotene on traumatic brain injury in mice
Brain Behavior and Immunity, 2017Co-Authors: Jianjun Zhong, Chongjie Cheng, Han Liu, Zhijian Huang, Hongrong Zhang, Li Jiang, Rami Darwazeh, Xiaochuan SunAbstract:Abstract Objective Bexarotene treatments exert neuroprotective effects on mice following traumatic brain injury (TBI). The present study aims to investigate the potential roles of the long noncoding RNA Neat1 in the neuroprotective effects of Bexarotene. Materials and methods Adult male C57BL/6J mice (n = 80) and newborn mice (within 24 h after birth) (n = 20) were used to generate a “controlled cortical impact” (CCI) model and harvest primary cortex neurons, respectively. The HT22 cell line and the BV2 cell line were cultured under “normal” or “oxygen/glucose-deprived” (OGD) conditions. The relationship between RXR-α and the Neat1 promoter was clarified using ChIP-qPCR and dual-luciferase reporter gene assays. The mRNA alterations induced by Neat1 knockdown were measured using next-generation RNA sequencing. Proteins were captured by Neat1, pulled down and subjected to mass spectrometry. The neurological severity score, rotarod test and water maze test were employed to measure the animals’ motor and cognitive functions. Results Bexarotene prominently up-regulated the Neat1 level in an RXR-α-dependent manner. Neat1 knockdown induced significant changes in mRNA expression, and the altered mRNAs were involved in many biological processes, including synapse formation and axon guidance. In primary neurons, Neat1 knockdown inhibited and Neat1 over-expression prompted axon elongation. Multiple proteins, including Pidd1, were captured by Neat1. Neat1 inhibited cell apoptosis and restricted inflammation by capturing Pidd1. The in vitro anti-apoptotic and anti-inflammatory effects of Neat1 were further confirmed in C57BL/6 mice, which resulted in better motor and cognitive function after TBI. Conclusion Bexarotene up-regulates the lncRNA Neat1, which inhibits apoptosis and inflammation, thereby resulting in better functional recovery in mice after TBI.
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Bexarotene protects against traumatic brain injury in mice partially through apolipoprotein e
Neuroscience, 2017Co-Authors: Jianjun Zhong, Chongjie Cheng, Han Liu, Zhijian Huang, Zhipeng Teng, Hongrong Zhang, Fang Cao, Li Jiang, Xiaochuan SunAbstract:Bexarotene has been proved to have neuroprotective effects in many animal models of neurological diseases. However, its neuroprotection in traumatic brain injury (TBI) is still unknown. This study aims to explore the neuroprotective effects of Bexarotene on TBI and its possible mechanism. Controlled cortical impact (CCI) model was used to simulate TBI in C57BL/6 mice as well as APOE gene knockout (APOE-KO) mice. After CCI, mice were daily dosed with Bexarotene or vehicle solution intraperitoneally. The motor function, learning and memory, inflammatory factors, microglia amount, apoptosis condition around injury site and main side-effects were all measured. The results showed that, after CCI, Bexarotene treatment markedly improved the motor function and spatial memory in C57BL/6 compare to APOE-KO mice which showed no improvement. The inflammatory cytokines, microglia amount, cell apoptosis rate, and protein of cleaved caspase-3 around the injury site were markedly upregulated after TBI in both C57BL/6 and APOE-KO mice, and all these upregulation were significantly mitigated by Bexarotene treatment in C57BL/6 mice, but not in APOE-KO mice. No side-effects were detected after consecutive administration. Taken together, Bexarotene inhibits the inflammatory response as well as cell apoptosis and improves the neurological function of mice after TBI partially through apolipoprotein E. This may make it a promising candidate for the therapeutic treatment after TBI.
Mary L Disis - One of the best experts on this subject based on the ideXlab platform.
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abstract 3687 Bexarotene activates type 1 antigen presenting cells increases tumor infiltrating cd8 t cells and augments the anti tumor activity of chemotherapy in breast cancer
Cancer Research, 2017Co-Authors: Sasha E Stanton, Ekram Gad, Lauren R Corullirastetter, Mary L DisisAbstract:Bexarotene is an oral rexinoic receptor (RXR) agonist that has anti-proliferative activity in breast cancer. RXRs are nuclear receptors that heterodimerize, including with the retinoic acid receptor (RAR), to activate transcription for processes including cellular differentiation, embryonic development, proliferation, and metabolism. We have demonstrated that Bexarotene can enhance cancer vaccine efficacy by synergizing with a multi-antigen vaccine to prevent breast cancer in the TgMMTV-neu model. Bexarotene as a single agent increased CD8 T-cell tumor infiltration. We therefore questioned the mechanism by which Bexarotene acted as an immunomodulatory drug. Evaluating RXR expression in human peripheral blood monocytes (PBMC) (n=10), we found that RXR is not expressed in NK T-cells or B-cells and in only a minority of CD4+ (5.1 ± 4%) and CD8+ T-cells (3.6 ± 3%). RXR, however, is expressed in 24.9±13% of macrophages, 38.6 ± 14% of plasmacytic dendritic cells (pDC), and 33.1 ± 16% of monocytic dendritic cells (mDC). PMBC treated with increasing doses of Bexarotene for 48 hours had increased co-stimulatory CD40 expression on mDC (p=0.0011 between 0 and 20 uM Bexarotene) and increased type 1 cytokine release including IL-1β (p=0.03 between 0 and 20 uM Bexarotene) and TNFα (p=0.02 between 0 and 20 uM Bexarotene) but not type 2 cytokine release of IL-10 (p=0.21) and IL-4 (p=0.5). These data demonstrate that Bexarotene can activate type 1 dendritic cells Since activated type 1 dendritic cells are effective at presenting tumor antigens from dying tumor cells, we wanted to determine if Bexarotene could increase type 1 immunity in the tumor and thereby enhance the efficacy of paclitaxel chemotherapy. In TgMMTV-neu mice with 100 mm3 established spontaneous tumors (n=5), 50 mg/kg Bexarotene inhibited tumor growth by 49% and increased the influx of intratumoral CD8+ T-cells by 61% as compared to PBS treated mice (p=0.01). 10 mg/kg paclitaxel inhibited tumor growth by 57% and increased intratumoral CD8+ T-cells by 45% as compared to PBS treated mice (p=0.003). Paclitaxel and Bexarotene together inhibited tumor growth by 83% (p=0.02 compared to Bexarotene or paclitaxel alone) and increased intratumoral CD8+ T-cell infiltrate by 58% as compared to PBS treated mice (p=0.01). Bexarotene could both activate type 1 APC and increase the CD8 T-cell infiltrate in the tumor and enhance the efficacy of paclitaxel. These data suggest concurrent adminstration of immunomodulatory Bexarotene with paclitaxel may result in augmentation of the anti-tumor activity of chemotherapy in breast cancer. Citation Format: Sasha Elizabeth Stanton, Ekram Gad, Lauren R. Corulli-Rastetter, Mary L. Disis. Bexarotene activates type 1 antigen presenting cells, increases tumor infiltrating CD8 T-cells, and augments the anti-tumor activity of chemotherapy in breast cancer [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 3687. doi:10.1158/1538-7445.AM2017-3687
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abstract 279 Bexarotene increases tumor cd8 t cells and improves response to conventional breast chemotherapy in the transgenic mouse mammary tumor model tgmmtv neu
Cancer Research, 2015Co-Authors: Sasha E Stanton, Edmond Marzbani, Lauren Rastetter, Ekram Gadd, Mary L DisisAbstract:In breast cancer, increased immune infiltrate prior to neoadjuvant chemotherapy predicts improved pathologic complete response (pCR) and improved survival, however almost half of breast tumors have no CD8+ T cell infiltrate. Evidence has emerged that conventional breast cancer chemotherapy can increase CD8+ T cells (doxorubicin) and decrease the immunosuppressive regulatory CD4+ T cells (paclitaxel and cyclophosphamide); therefore discovering well tolerated agents that further enhance the anti-tumor immune function of these chemotherapies may further improve response in breast cancer patients. The oral agent Bexarotene (a retinoic receptor agonist) showed a 20% disease response as a single agent in metastatic breast cancer and has been shown to increase CD8+ T cell tumor infiltration and decrease CD8+ T cell apoptosis in vitro. The goal of this study is to demonstrate whether this well tolerated oral agent can enhance the anti-tumor response of conventional chemotherapy through increasing intratumoral CD8+ T cells in TgMMTV-neu transgenic mice that are immunologically competent and genetically similar to human luminal B breast cancer. Two of the most active chemotherapies in human breast cancer, doxorubicin and paclitaxel, each could inhibit tumor growth by 70-80% and increase CD8+ T cell tumor infiltrate by approximately 40% in tumor bearing TgMMTV-neu mice, a third breast cancer chemotherapy cyclophosphamide increased CD8+ tumor infiltrate by 45% (p = 0.011) but did not show a statistically significant decrease in tumor volume. When TgMMTV-neu mice with ∼100 mm3 tumors were treated with 50 mg/m2 Bexarotene for four weeks they demonstrated a 44% increase in CD8+ tumor infiltrate (p = 0.05) and 60% decrease in mean tumor growth (p = 0.03) compared to control. However, the addition of Bexarotene to chemotherapy was superior to chemotherapy alone, and significantly more effective than Bexarotene alone. This enhanced anti-tumor function was even seen with cyclophosphamide that by itself had not inhibited tumor growth. Adding Bexarotene to weekly doxorubicin decreased tumor growth by 98% (p = 0.008 compared to doxorubicin alone), adding Bexarotene to weekly paclitaxel decreased tumor growth by 86% (p = 0.02 compared to paclitaxel alone), and adding Bexarotene to weekly cyclophosphamide inhibited tumor growth by 82% (p = 0.04 compared to cyclophosphamide alone). Further studies are now ongoing to identify the anti-tumor role of Bexarotene particularly its immune modulatory role. These results suggest that the addition of Bexarotene, a relatively well-tolerated oral agent, may modify the immune environment and improve tumor response to chemotherapy in breast cancer possibly improving response to neoadjuvant chemotherapy. Citation Format: Sasha E. Stanton, Ekram Gadd, Edmond Marzbani, Lauren Rastetter, Mary L. Disis. Bexarotene increases tumor CD8+ T cells and improves response to conventional breast chemotherapy in the transgenic mouse mammary tumor model TgMMTV-neu. [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 279. doi:10.1158/1538-7445.AM2015-279
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abstract p5 04 06 oral immunomodulatory agents prevent tumor growth and increase tumor cd8 t cell infiltrate Bexarotene further improves tumor response to conventional chemotherapy in breast tumors
Cancer Research, 2015Co-Authors: Sasha E Stanton, Ekram Gad, Edmond Marzbani, Lauren Rastetter, Mary L DisisAbstract:The tumor immune environment is important in breast cancer with greater than 50% immune infiltrate (LPBC) prior to neoadjuvant chemotherapy predicting improved pathologic complete response, and LPBC and CD8 infiltrate prior to adjuvant therapy predicting improved survival. Unfortunately, the majority of breast cancers do not have LPBC or robust CD8+ infiltrate. Evidence has emerged that conventional chemotherapy can increase CD8+ T cells therefore discovering ways to boost this response should further enhance the anti-tumor function. Three oral agents have modest anti-tumor function: metformin (oral biguanide), Bexarotene (retinoic receptor agonist), and celecoxib (COX2 inhibitor). In vitro data suggest a role for these agents in increasing Th1 immunity: metformin was shown to increase MHC class I expression on tumor cells, Bexarotene was shown to decrease CD8+ T cell apoptosis, and celecoxib has been shown to decrease MDSC cells. The goal of this study was to demonstrate whether addition of these oral agents to conventional chemotherapy enhanced the anti-tumor function of chemotherapy, possibly by modifying the immune environment in the transgenic mouse mammary tumor model TgMMTV-neu (genetically similar to luminal breast cancer). Two active chemotherapies in human breast cancer, doxorubicin and paclitaxel, inhibited tumor growth and increased CD8+ T cell tumor infiltrate in transgenic mice. Treatment of mice with 100 mm3 tumors with doxorubicin (5 mg/kg weekly for four weeks) showed a 32% increase in CD8+ T cells and 85% decrease in tumor growth as compared to control mice (p=0.0001) and treatment with paclitaxel (10 mg/kg weekly for four weeks) showed a 40% increase in CD8+ tumor infiltrate (p=0.0068) and 60% decrease in tumor growth as compared to control treated mice (p=0.0026). A third chemotherapy cyclophosphamide (100 mg/kg weekly for four weeks) increased CD8+ tumor infiltrate by 45% (p=0.011) but did not show a significant decrease in tumor volume (p=0.57). Metformin and Bexarotene also demonstrated increased CD8+ tumor infiltration and decreased breast tumor growth but celecoxib did not. Metformin treated mice had a 46% increase in CD8+ tumor infiltrate (p=0.001) and a 52% decrease in mean tumor volume (p=0.011) as compared to controls (75 mg/m2 of metformin for four weeks). Bexarotene treated mice had 44% increase in CD8+ tumor infiltrate (p=0.05) and 60% decrease in mean tumor growth (p=0.03) compared to control (treated with 50 mg/m2 Bexarotene for four weeks). Of all three oral therapies, Bexarotene was most effective inhibiting spontaneous tumor growth in the mice. Furthermore, addition of Bexarotene to chemotherapy was superior to chemotherapy alone. Adding Bexarotene to weekly doxorubicin decreased tumor growth by 98% (p=0.008 compared to doxorubicin alone), adding Bexarotene to weekly paclitaxel decreased tumor growth by 86% (p=0.02 compared to paclitaxel alone), and adding Bexarotene to weekly cyclophosphamide inhibited tumor growth by 82% (p=0.04 compared to cyclophosphamide alone). These results suggest that addition of Bexarotene, a well-tolerated oral agent, to chemotherapy may improve tumor response in breast cancer. Citation Format: Sasha E Stanton, Ekram Gad, Edmond Marzbani, Lauren Rastetter, Mary L Disis. Oral immunomodulatory agents prevent tumor growth and increase tumor CD8 T cell infiltrate; Bexarotene further improves tumor response to conventional chemotherapy in breast tumors [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-04-06.