Promontory Therapeutics Announces Peer-Reviewed Cancer Publication of Selective Effects of PT-112 in Cancer Cell Models Induced by Mitochondrial Dysfunction
In vitro study investigated the mechanisms underlying the cancer cell killing effects of PT-112 in mouse tumor cells with well characterized mitochondrial and metabolic status
Data showed that PT-112 induces mitochondrial stress and immunogenic cell death (ICD) in tumor cells with mitochondrial deficiencies
NEW YORK, August 11, 2022 /PRNewswire/ — Promontory Therapeutics Inc.a clinical-stage pharmaceutical company focused on oncology therapeutics, today announced the publication of peer-reviewed mechanistic studies with lead candidate PT-112 in this month’s issue of Cancer (volume 14, number 16), a publication of the MDPI. The in vitro The study, titled “PT-112 induces mitochondrial stress and immunogenic cell death, targeting tumor cells with mitochondrial deficiencies,” showed that PT-112 was selective for cells with defective mitochondria, inducing tumor cell death. cancer cells by unconventional mechanisms, including increased mitochondrial stress. , generation of free radicals and immunogenic cell death (ICD), a form of cell death that depends on cellular stresses and elicits an immune response.
PT-112, in Phase 1/2 clinical development, has shown clinical activity against pretreated advanced solid tumors and has been shown to induce robust ICD. This manuscript reports the anticancer activity of PT-112, including mitochondrial stress and the selectivity of cancer metabolic processes, in particular mitochondrial dysfunction.
Key findings include:
- Mouse tumor cells with mitochondrial DNA mutations and resulting glycolytic phenotype were more susceptible to PT-112-induced cell death compared to cells with an intact oxidative phosphorylation pathway (OXPHOS)
- PT-112 induced mitochondrial stress and initiated autophagy, which is associated with an integrated stress response and subsequent ICD
- PT-112 caused exposure to calreticulin, further confirming the DAI effects of PT-112
- HIF-1α expression was higher in PT-112 sensitive cells
- Such selectivity of PT-112 has the potential for clinical applications in metabolically aggressive cancers.
Our study published in Cancer provides evidence for PT-112-induced cancer cell organelle stresses and their relationship to ICD“, said Matthew Price, executive vice president and chief operating officer of Promontory Therapeutics. “These findings are part of ongoing efforts across multiple research collaborations to define the causes of the known immunogenic effects of PT-112, and support the uniqueness of its mechanism of action.”
Full results are available in the journal Cancer and online here.
About the PT-112
PT-112 is the first pyrophosphate conjugated small molecule in oncology and has a unique pleiotropic mechanism of action that promotes immunogenic cell death (ICN), through the release of damage-associated molecular patterns (DAMPs) that bind to dendritic cells and lead to the recruitment of immune effector cells downstream into the tumor microenvironment. PT-112 represents a very potent inducer of this immunological form of cancer cell death. Additionally, PT-112 harbors a property known as osteotropism, or the drug’s propensity to reach its highest concentrations in certain areas of bone, making it a candidate for treating patients with cancers that originate or metastasize to bone. . First-in-man study of PT-112 demonstrated an attractive safety proﬁle and evidence of durable responses in heavily pretreated patients and won the “Best Poster” award in the Developmental Therapeutics category at the 2018 Annual Meeting from ESMO. The combination phase 1b The dose-escalation study of PT-112 with the PD-L1 checkpoint inhibitor avelumab in solid tumors was reported during an oral presentation at the Virtual ESMO Congress 2020. The phase study 1 in patients with relapsed or refractory multiple myeloma presented at ASH is the third completed Phase 1 study of PT-112. Phase 2 monotherapy development is ongoing in mCRPC and now includes the Phase 2 proof-of-concept study in thymic epithelial tumors as part of the company’s formal collaboration with the NCI. The Phase 2a study of the PD-L1 combination is ongoing in a dose confirmation cohort of patients with non-small cell lung cancer (NSCLC).
About Promontory Therapeutics
Promontory Therapeutics Inc. is a privately held, clinical-stage pharmaceutical company specializing in small molecule immunotherapy. The Company’s lead candidate, PT-112, is the first conjugated pyrophosphate small molecule in oncology and has a unique pleiotropic mechanism of action that promotes immunogenic cell death (ICD), through the release of damage-associated molecular patterns (DAMP) that bind to pattern recognition receptors on dendritic cells and promote adaptive immune response in the tumor microenvironment. Clinical data generated from three phase 1 studies demonstrated anticancer activity as monotherapy and an attractive safety profile, and three phase 2 studies with PT-112 are ongoing. The company’s research and development work has been carried out in United States, Europe and Asiaas well as a sublicense agreement for the development, commercialization and use of PT-112 in Greater China. The company is also sponsoring 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 United States and Canada), and has an active Phase 2 trial underway with the NCI using 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.
Taylor B. Young
Senior Director, Strategic Development
Tel: +1 646 380 2441
E-mail: [email protected]
Tel: +1 646 277 1282
E-mail: [email protected]
Tel: +1 203 682 8288
E-mail: [email protected]
SOURCE Promontory Therapeutics Inc.