On November 11, 2022 Promontory Therapeutics Inc., a clinical stage pharmaceutical company advancing small molecule immunotherapies in oncology, reported data on lead therapeutic candidate PT-112 and its immunological effects on cancer cell mitochondria at the 34th Annual Meeting of the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) (Press release, Promontory Therapeutics, NOV 11, 2022, View Source [SID1234623835]). The poster titled, "Immunologically relevant effects of PT-112 on cancer cell mitochondria" demonstrated that PT-112 caused anti-cancer activity, which is related to its ability to induce immunogenic cell death (ICD).

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"Under our ongoing collaboration with the lab of Lorenzo Galluzzi, PhD, Weill Cornell Medical College, we are exploring how PT-112 impacts on cancer cell mitochondria in the context of immunogenic cell death," said Matthew Price, Promontory Therapeutics co-founder and Chief Operating Officer. "The data presented at SITC (Free SITC Whitepaper) further confirm that PT-112 induces mitochondrial dysfunction in cancer cells, with two key insights: that PT-112 causes the accumulation of mitochondrial (mt)DNA in the cytosol, a phenomenon referred to as ‘viral mimicry’; and that PT-112 could drive immunogenic signaling before the induction of cancer cell death – both consistent with the understanding of ICD. These findings are particularly important as PT-112 progresses through clinical development."

PT-112 is under Phase 2 clinical development for metastatic castration-resistant prostate cancer, thymoma and thymic carcinoma, and non-small cell lung cancer. In addition to mediating cytostatic and cytotoxic effects in a variety of human and mouse cancer cell lines, PT-112 elicits multiple damage-associated molecular patterns (DAMPs), linked to immunogenic cancer cell death. Findings from the study include:

PT-112 causes pronounced mitochondrial dysfunction in cancer cells, coupled with the accumulation of mtDNA in the cytosol.

PT-112-driven reactive oxygen species production is mediated in part by a BAX/BAK1-dependent pathway, further indicative of mitochondrial involvement.

Functional BAX/BAK1 and CASP3, but not CASP2, render mouse cancer cells susceptible to PT-112-induced cell death.

CASP3 activation appears to limit interferon secretion by mouse cancer cells responding to PT-112, suggesting that interferon release may not be required in PT-112-induced ICD in this model system, as observed previously and reported in OncoImmunology.

SITC abstracts are available for viewing here.

For more information about PT-112 and Promontory Therapeutics’ clinical pipeline visit www.PromontoryTx.com.

About PT-112

PT-112 is the first small-molecule conjugate of pyrophosphate in oncology, and possesses a unique pleiotropic mechanism of action that promotes immunogenic cell death (ICD), through the release of damage associated molecular patterns (DAMPs) that bind to dendritic cells and lead to downstream immune effector cell recruitment in the tumor microenvironment. PT-112 represents a highly potent inducer of this immunological form of cancer cell death. Further, PT-112 harbors a property known as osteotropism, or the propensity of the drug to reach its highest concentrations in certain areas of the bone, making it a candidate for treatment of patients with cancers that originate in, or metastasize to, the bone. The first in-human study of PT-112 demonstrated an attractive safety profile and evidence of long-lasting responses among heavily pre-treated patients and won "Best Poster" within the Developmental Therapeutics category at the ESMO (Free ESMO Whitepaper) 2018 Annual Congress. The combination Phase 1b dose escalation study of PT-112 with PD-L1 checkpoint inhibitor avelumab in solid tumors was reported in an oral presentation at the ESMO (Free ESMO Whitepaper) 2020 Virtual Congress. The Phase 1 study in patients with relapsed or refractory multiple myeloma presented at ASH (Free ASH Whitepaper) is the third completed Phase 1 study of PT-112. Monotherapy Phase 2 development is ongoing in mCRPC, and now includes the Phase 2 proof of concept study in thymic epithelial tumors under the company’s formal collaboration with the NCI. The PD-L1 combination Phase 2a study is ongoing in a dose confirmation cohort of non-small cell lung cancer (NSCLC) patients.