Promontory Therapeutics Announces Peer-Reviewed Publication in Cancers of Selective Effects of PT-112 in Cancer Cell Models Driven by Mitochondrial Dysfunction
In vitro study investigated the mechanisms underlying PT-112's cancer cell death effects in mouse tumor cells with well-characterized mitochondrial and metabolic status
Data showed PT-112 induces mitochondrial stress and immunogenic cell death (ICD) in tumor cells with mitochondrial deficiencies
NEW YORK, Aug. 11, 2022 /PRNewswire/ -- Promontory Therapeutics Inc., a clinical stage pharmaceutical company focused on oncology therapeutics, announced today the peer-reviewed publication of mechanistic studies with lead candidate PT-112 in this month's issue of Cancers (volume 14, issue 16), an MDPI publication. The in vitro study, entitled "PT-112 induces mitochondrial stress and immunogenic cell death, targeting tumor cells with mitochondrial deficiencies," showed that PT-112 was selective to cells with defective mitochondria, inducing cancer cell death through non-conventional mechanisms, including increased mitochondrial stress, free radical generation, and immunogenic cell death (ICD), a form of cell death that is reliant upon cellular stresses, and elicits an immune response.
PT-112, under phase 1/2 clinical development, has shown clinical activity against advanced pretreated solid tumors and has been shown to induce robust ICD. This manuscript reports PT-112's anti-cancer activity, including mitochondrial stress and selectivity to cancer metabolic processes, specifically mitochondrial dysfunction.
Key findings include:
- Mouse tumor cells presenting mitochondrial DNA mutations and the resulting glycolytic phenotype were more sensitive to cell death induced by PT-112 compared to cells with an intact oxidative phosphorylation (OXPHOS) pathway
- PT-112 induced mitochondrial stress and initiated autophagy, which is associated with an integrated stress response and with subsequent ICD
- PT-112 caused calreticulin exposure, further substantiating PT-112's ICD effects
- HIF-1α expression was higher in cells sensitive to PT-112
- Such selectivity of PT-112 has the potential for clinical applications in metabolically aggressive cancers
"Our study published in Cancers provides evidence of PT-112-induced cancer cell organelle stresses, and their relationship to ICD," said Matthew Price, Executive VP & COO of Promontory Therapeutics. "These findings are part of ongoing efforts crossing several research collaborations to define the causes of PT-112's known immunogenic effects, and are supportive of the uniqueness of its mechanism of action."
The full results are available in the journal Cancers and online here.
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 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 2020 Virtual Congress. The Phase 1 study in patients with relapsed or refractory multiple myeloma presented at ASH 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.
About Promontory Therapeutics
Promontory Therapeutics Inc. is a privately held, clinical stage pharmaceutical company focused on small molecule immunotherapy. The company's lead candidate, 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 pattern recognition receptors on dendritic cells and promote the adaptive immune response in the tumor microenvironment. Clinical data generated across three Phase 1 studies have demonstrated single-agent anti-cancer activity and an attractive tolerability profile, and three Phase 2 studies of PT-112 are underway. The company's research and development work has been conducted in the United States, Europe and Asia, along with a sub-license agreement for the development, commercialization and use of PT-112 in Greater China. The company also sponsors the ongoing clinical study of PT-112 in combination with the PD-L1 inhibitor avelumab under a collaboration agreement with Pfizer and Merck KGaA, Darmstadt, Germany (operating as EMD Serono in the US and Canada), and has an active Phase 2 trial underway with the NCI utilizing PT-112 in thymic epithelial tumors where PT-112 has received Orphan Drug designation.
To learn more about Promontory Therapeutics, visit the company's website here.
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SOURCE Promontory Therapeutics Inc.
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