Everolimus and pazopanib (E/P) benefit genomically selected patients with metastatic urothelial carcinoma

Bellmunt, Joaquim; Lalani, Aly-Khan A.; Jacobus, Sussana; Wankowicz, Stephanie A.; Polácek, L; Takeda, David Y.; Harshman, Lauren C.; Wagle, Nikhil; Moreno, Irene; Lundgren, Kevin; Bossé, Dominick; Allen, Eliezer M. Van; Choueiri, Toni K.; Rosenberg, Jonathan E.

doi:10.1038/s41416-018-0261-0

Cited by 32 publications

(24 citation statements)

References 39 publications

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“…A recent report in a melanoma patient experiencing kidney allograft rejection following PD‐1 blockade suggests that mTOR inhibitors can increase tolerogenic mechanisms against nontumoral tissue at the same time preserving the activity of checkpoint inhibitors 65 . This observation, coupled with the recent findings that pazopanib and mTOR inhibitors can be particularly effective in tumors bearing specific genetic alterations (mTOR and FGFR pathway mutations) offer the opportunity to study additional combinatorial approaches in selected patient populations 66 …”

Section: Discussionmentioning

confidence: 99%

“…65 This observation, coupled with the recent findings that pazopanib and mTOR inhibitors can be particularly effective in tumors bearing specific genetic alterations (mTOR and FGFR pathway mutations) offer the opportunity to study additional combinatorial approaches in selected patient populations. 66 To perform our analyses, we collected peripheral blood before and 3-6 months after treatment intiation. These time points were chosen considering findings and limitations of relevant investigations in this context.…”

Section: Discussionmentioning

confidence: 99%

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Integrated transcriptional‐phenotypic analysis captures systemic immunomodulation following antiangiogenic therapy in renal cell carcinoma patients

Rinchai

Verzoni

Huber

et al. 2021

Clinical & Translational Med

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Background:The combination of immune checkpoint blockade (ICB) with standard therapies is becoming a common approach for overcoming resistance to cancer immunotherapy in most human malignancies including metastatic renal cell carcinoma (mRCC). In this regard, insights into the immunomodulatory properties of antiangiogenic agents may help designing multidrug schedules based on specific immune synergisms. Methods: We used orthogonal transcriptomic and phenotyping platforms combined with functional analytic pipelines to elucidate the immunomodulatory effect of the antiangiogenic agent pazopanib in mRCC patients. Nine patients were studied longitudinally over a period of 6 months. We also analyzed transcriptional data from The Cancer Genome Atlas (TCGA) RCC cohort (N = 571

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Integrated transcriptional‐phenotypic analysis captures systemic immunomodulation following antiangiogenic therapy in renal cell carcinoma patients

Rinchai

Verzoni

Huber

et al. 2021

Clinical & Translational Med

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“…Blockade of angiogenesis in two different pathways with an mTOR inhibitor and a VEGFR inhibitor has been demonstrated to increase anti-tumor efficacy against several cancers in preclinical and clinical studies 15 , 47 – 49 . The combination of an mTOR and VEGFR inhibitor demonstrated 3.6 months progression free survival and 9.1 months overall survival in a urothelial carcinoma clinical trial 15 . In the present study, the efficacy of the mTOR and VEGFR inhibitor combination on osteosarcoma is the first report to the best of our knowledge.…”

Section: Discussionmentioning

confidence: 99%

“…The efficacy of the combination of mTOR and VEGFR inhibitors was reported in pleural mesothelioma and urothelial carcinoma 14 , 15 . However, this combination has not been evaluated on osteosarcoma.…”

Section: Introductionmentioning

confidence: 99%

An mTOR and VEGFR inhibitor combination arrests a doxorubicin resistant lung metastatic osteosarcoma in a PDOX mouse model

Oshiro

Tome

Miyake

et al. 2021

Sci Rep

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In order to identify more effective therapy for recalcitrant osteosarcoma, we evaluated the efficacy of an mTOR-VEGFR inhibitor combination on tumor growth in a unique osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model derived from the lung metastasis of an osteosarcoma patient who failed doxorubicin therapy. We also determined the efficacy of this inhibitor combination on angiogenesis using an in vivo Gelfoam fluorescence angiogenesis mouse model implanted with osteosarcoma patient-derived cells (OS-PDCs). PDOX models were randomly divided into five groups of seven nude mice. Group 1, control; Group 2, doxorubicin (DOX); Group 3, everolimus (EVE, an mTOR and VEGF inhibitor); Group 4, pazopanib (PAZ, a VEGFR inhibitor); Group 5, EVE-PAZ combination. Tumor volume and body weight were monitored 2 times a week. The in vivo Gelfoam fluorescence angiogenesis assay was performed with implanted OS-PDCs. The nude mice with implanted Gelfoam and OSPDCs also were divided into the four therapeutic groups and vessel length was monitored once a week. The EVE-PAZ combination suppressed tumor growth in the osteosarcoma PDOX model and decreased the vessel length ratio in the in vivo Gelfoam fluorescent angiogenesis model, compared with all other groups (p < 0.05). There was no significant body-weight loss in any group. Only the EVE-PAZ combination caused tumor necrosis. The present study demonstrates that a combination of an mTOR-VEGF inhibitor and a VEGFR inhibitor was effective for a DOX-resistant lung-metastatic osteosarcoma PDOX mouse model, at least in part due to strong anti-angiogenesis efficacy of the combination.

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“…A phase I study investigating the mTOR inhibitor everolimus combined with the vascular endothelial growth factor RTK (VEGFR) inhibitor pazopanib showed a favorable toxicity profile and clinical benefit was observed in 4 of 19 included patients with mUC harboring TSC1/TSC2 mutations [44]. Two PIK3CA inhibitors are also included in the MATCH basket trial: copanlisib (BAY 80-6946) for patients with Pi3KCA-activating mutations and or PTEN-inactivating mutations, and GSK2636771 for patients with PTEN-inactivating mutations (NCT02465060).…”

Section: Mapk and Pi3k/akt/mtor Pathway Alterationsmentioning

confidence: 99%

Targeted Therapy in Metastatic Bladder Cancer: Present Status and Future Directions

et al. 2020

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The recommended treatment for metastatic urothelial carcinoma (mUC) patients is platinum-based chemotherapy. Although initial response rates are moderate, the vast majority of patients experience a relapse due to chemoresistance and eventually succumb to their disease. Furthermore, platinum-based chemotherapy is toxic and approximately 30% of mUC patients are unfit for chemotherapy. Thus, there is a clear unmet need for novel, more efficacious treatment options in mUC with a safer toxicity profile. To propel the advancement of novel treatment options, we present a summary of key signaling pathways and molecular mechanisms that are known to be involved in bladder cancer tumorigenesis with a focus on promising candidate druggable molecular targets and innovative targeted therapies currently under clinical investigation. Targetable alterations were mainly described in fibroblast growth factor receptor (FGFR) and epidermal growth factor receptor (ErbB) tyrosine kinase receptor (RTK) families, downstream pathways, and chromatin remodelers, which are major bladder cancer driver genes. Drugs targeting the FGFR family members are emerging as personalized treatment options for selected mUC patients with tumor-specific FGFR alterations. The pan-FGFR inhibitor, erdafitinib, was first-in-class to receive U.S. Food and Drug Administration (FDA) approval in 2019, while inhibitors of ErbB family members have shown less potential. Antibody-drug conjugates (ADCs) are a class of targeted therapeutics that deliver cytotoxic drugs in close proximity to cancer cells by targeting RTKs or other transmembrane proteins. Enfortumab vedotin is the first-in-class ADC that was FDA approved for the treatment of locally advanced or mUC in 2019.

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Everolimus and pazopanib (E/P) benefit genomically selected patients with metastatic urothelial carcinoma

Abstract: Combination therapy with E/P is safe in mUC and select patients with alterations in mTOR or FGFR pathways derive significant clinical benefit.

Cited by 32 publications

References 39 publications

Integrated transcriptional‐phenotypic analysis captures systemic immunomodulation following antiangiogenic therapy in renal cell carcinoma patients

Integrated transcriptional‐phenotypic analysis captures systemic immunomodulation following antiangiogenic therapy in renal cell carcinoma patients

An mTOR and VEGFR inhibitor combination arrests a doxorubicin resistant lung metastatic osteosarcoma in a PDOX mouse model

Targeted Therapy in Metastatic Bladder Cancer: Present Status and Future Directions

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