On April 19, 2016 Peloton Therapeutics, Inc., a drug discovery and development company focused on advancing first-in-class, small molecule cancer therapies targeting unexploited molecular vulnerabilities, reported preclinical data on its lead investigational candidate, PT2385, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, LA (Press release, Peloton Therapeutics, APR 19, 2016, View Source [SID:1234511099]). PT2385 is the first clinical stage antagonist of hypoxia inducible factor-2α (HIF-2α), a transcription factor implicated in the development and progression of renal and other cancers.
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"PT2385, a Novel HIF-2α Antagonist, Combines with Checkpoint Inhibitor Antibodies to Inhibit Tumor Growth in Preclinical Models by Modulating Myeloid Cells and Enhancing T Cell Infiltration"
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In addition to its direct role in transcription regulation of growth-promoting genes in renal tumors, HIF-2α has been proposed to affect the tumor microenvironment. In a poster titled "PT2385, a Novel HIF-2α Antagonist, Combines with Checkpoint Inhibitor Antibodies to Inhibit Tumor Growth in Preclinical Models by Modulating Myeloid Cells and Enhancing T Cell Infiltration," the combination of PT2385 with antibodies to immune checkpoint control molecules (PD-1, PD-L1, and CTLA4) yielded additive or synergistic efficacy in preclinical tumor models. HIF-2α is not detected in the mouse tumor cells, but is expressed in the stroma. Tumor growth inhibition by these combination regimens was accompanied by modulation of a variety of immune markers such as infiltrating T-cells, macrophage and myeloid-derived suppressor cell populations in the tumors. The combination of PT2385 and immune checkpoint inhibitors is planned for evaluation in clinical trials.
"PT2385 has now been shown to affect the tumor microenvironment, even for tumors that do not express HIF-2α. This potentially broadens the applicability of PT2385 to a larger variety of tumor types, including melanoma and lung cancers, which have been shown to have a strong immunological component," said John Josey, Ph.D., Peloton’s Chief Executive Officer.
About PT2385
PT2385 is a first-in-class small molecule inhibitor of hypoxia-inducible factor-2α (HIF-2α), a transcription factor implicated in the development and progression of kidney cancer. It is currently being investigated in a Phase 1 clinical trial for the treatment of advanced or metastatic clear cell renal cell carcinoma (ccRCC). Loss of the von Hippel-Lindau tumor suppressor (VHL) is the key oncogenic event in up to 95% of patients with ccRCC. With the loss of the VHL protein (pVHL), the transcription factor HIF-2α accumulates and drives the unbalanced expression of numerous gene products. Preclinical data indicate that orally bioavailable PT2385 disrupts HIF-2α activity in ccRCC and thereby blocks the expression of multiple tumorigenic factors responsible for unrestrained cancer cell growth and proliferation, tumor angiogenesis, and suppression of anti-tumor immune responses characteristic of ccRCC.
About Renal Cell Cancer
The American Cancer Society estimates that more than 62,000 new cases of kidney cancer will be diagnosed and more than 14,000 people will die from this disease this year. The National Cancer Institute reports that the prognosis for any treated renal cell cancer patient with progressing, recurring, or relapsing disease is poor, regardless of cell type or stage.