PT-112’s mechanism of action promotes immunogenic cancer cell death through ribosomal biogenesis inhibition and organelle stress
NEW YORK, Oct. 14, 2023 /PRNewswire/ — Promontory Therapeutics Inc., a clinical stage biotech company advancing immunogenic small molecule approaches in oncology, today presented data on its lead therapeutic candidate PT-112, detailing its early molecular effects that culminate in immunogenic cancer cell death (ICD). The presentation was made at the American Association for Cancer Research (AACR) – National Cancer Institute (NCI) – European Organisation for Research and Treatment of Cancer (EORTC) International Conference on Molecular Targets and Cancer Therapeutics, taking place October 11-15, 2023 in Boston.
The study was designed to clarify early molecular effects of PT-112 that are known to culminate in ICD by assessing nucleolar protein phenotypes in human prostate cancer cells treated with PT-112 using antibody labeling, followed by confocal microscopy. Researchers also conducted nascent RNA sequencing in human cancer cells (non-small cell lung, prostate and renal cell carcinoma) following one and six hours of PT-112 treatment.
“Our study shows that PT-112 inhibits ribosomal biogenesis in cancer cells. This was observed in all the cell lines assessed after short exposure durations, indicating it is central to PT-112’s mechanism of action and its ability to induce selective immunogenic cancer cell death,” said Tyler Ames, PhD, Promontory Therapeutics Senior Vice President of Research and Development. “While further validation of these findings is ongoing, this work deepens our understanding of PT-112’s specific molecular effects. The present findings, together with prior validation of its ICD effects, and evidence of durable clinical activity of PT-112, position it as a promising small molecule cancer immunotherapy.”
Study findings include:
- PT-112 rapidly causes ribosomal biogenesis (RiBi) inhibition and nucleolar stress, likely driving previously observed PT-112-induced cancer organelle stresses and ICD.
- At early timepoints in prostate cancer cells, PT-112 caused evident nucleolar protein translocation, a hallmark of nucleolar stress and disruption of RiBi.
- Consistent with the above, PT-112 induced statistically significant repression of pathways related to RiBi, ribosomal RNA (rRNA) processing and translation, crossing prostate, renal and lung cancer cell lines. Notably, a pattern across these pathways was the reduced expression of many ribosomal genes, consistent with RiBi inhibition.
Collaborating with the Baylor College of Medicine and with Arpeggio Biosciences in Boulder, Colorado, the Promontory research team used confocal microscopy and nascent RNA sequencing, and performed analysis using Enrichr across multiple databases to identify biological pathways linked to clusters of differentially expressed genes (p ≤ 0.001) in PT-112-treated cells.
PT-112 is currently in Phase 2 clinical trials in a late-line setting of metastatic castration-resistant prostate cancer, and in thymic epithelial tumors. The latter study is led by the National Cancer Institute under a formal collaboration.
For more information about Promontory Therapeutics and PT-112, visit www.PromontoryTx.com.
About PT-112
PT-112 is the first small-molecule conjugate of pyrophosphate in clinical development in oncology. PT-112 has numerous advantages — including its tolerability and inhibition of ribosomal biogenesis (RiBi) which leads to 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 data were published in eClinicalMedicine, part of The Lancet. The combination Phase 1b dose escalation study of PT-112 with PD-L1 checkpoint inhibitor avelumab in solid tumors was reported in a mini-oral presentation at the ESMO 2020 Virtual Congress and the Phase 2a dose confirmation cohort in non-small cell lung cancer (NSCLC) patients was reported at ESMO I-O 2022. The Phase 1 study in patients with relapsed or refractory multiple myeloma presented at ASH 2020 is the third completed Phase 1 study of PT-112. Monotherapy Phase 2 development is ongoing in mCRPC, and includes the Phase 2 proof of concept study in thymic epithelial tumors under the company’s formal CRADA with the NCI. Preliminary data from the NCI study were published at ASCO 2023 and at the ITMIG 2023 annual meeting, and show evidence of anti-cancer immune activation by PT-112.
About Promontory Therapeutics
Promontory Therapeutics Inc. is a privately held, clinical stage drug development company focused on small molecule immunotherapy in cancer. Clinical data generated across three Phase 1 studies of lead molecule PT-112 have demonstrated single-agent and combination anti-cancer activity and an attractive tolerability profile. The Company’s lead Phase 2 study in late-stage metastatic castration-resistant prostate cancer patients is underway in the United States and France. The company applies a borderless collaboration model for research and development work, which has been conducted in the United States, Europe and Asia. As part of its recent expansion into France, Promontory was selected as the first international company member of the Paris-Saclay Cancer Cluster, Europe’s emerging biotech hub for oncology. The company also has an active Phase 2 trial underway with the National Cancer Institute utilizing PT-112 in thymic epithelial tumors (TETs), a rare disease with no FDA approved drug, for which PT-112 has received FDA Orphan Drug designation.
To learn more about Promontory Therapeutics, visit the company’s website here.
CONTACTS:
Promontory Therapeutics
Brooke Raphael, MS
VP, Strategy & Operations
Tel: +1 (646) 974-6453
Email: [email protected]
Investors:
Stan Musial
Tel: +1 (646) 222-6932
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ICR Westwicke
Media:
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SOURCE Promontory Therapeutics Inc.
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