New data about the molecular mechanisms of PT-112's showed immunogenic effects that inhibit ribosomal biogenesis, promoting immunogenic cancer cell death through cancer cell organelle stresses.
New York:
Biotech company Promontory Therapeutics presented data demonstrating the molecular mechanism of its lead therapeutic candidate, PT-112, and its ability to induce immunogenic cell death (ICD) in cancer cells.
The demonstration was made at the Society for Immunotherapy of Cancer's (SITC) 38th Annual Meeting, taking place November 1–5, 2023, in San Diego.
The company, working on immunogenic small molecule approaches in oncology, suggests that PT-112-induced ICD is mediated by endoplasmic reticulum (ER) and mitochondrial stresses, which are specific intra-cellular events that comprise part of the larger ICD mechanism.
According to the Promontory Therapeutics presentation, the work was designed in collaboration with the Galluzzi Lab at Weill Cornell Medical College in New York in order to elucidate the sequence of events—beginning with inhibition of ribosomal biogenesis and culminating in selective ICD—underlying PT-112's immune effects.
Analyzing a panel of mouse cell lines engineered to lack specific genes involved in mitochondrial apoptosis (Bcl2, Bax, and Bak1), flow cytometry, immunoblotting, RT-PCR, and immunofluorescence microscopy were used to point out the response of PT-112 to ER and mitochondrial stress, as well as immunogenic signaling.
"Our ongoing studies of PT-112 provide mechanistic insights for this promising immunogenic small molecule, which has shown clinical activity in patients with a variety of cancers," said Promontory Therapeutics Senior Vice President of Research and Development Tyler Ames, PhD. "This particular work sheds light on how PT-112 encourages the immunogenic cell death of cancerous cells through ER stress and mitochondrial dysfunction, both of which are known to contribute to immune signaling."
Study findings include that PT-112 drives ER stress and mitochondrial dysfunction, which promote ICD; PT-112 effects on mitochondria include increases in mitochondrial mass and reactive oxygen species, changes in membrane polarization, and the release of mitochondrial DNA into the cytosol, a potent immunogenic signal. Some of these effects were impacted by the absence of Bax and Bak1.
Also, PT-112 elicits the phosphorylation of eukaryotic translation initiation factor 2 subunit alpha (EIF2S1, best known as eIF2α), indicating ER stress and the activation of the integrated stress response (ISR).
In addition, there is an increase in the levels of Ifnb1 mRNA after PT-112 exposure, indicating PT-112 induces type 1 interferon responses.
Moreover, PT-112 is the subject of ongoing Phase 2 clinical trials for metastatic castrate-resistant prostate cancer and thymic epithelial tumors and a completed Phase 2a trial in non-small cell lung cancer. In previous mechanism of action research, data showed that PT-112 causes ribosomal biogenesis inhibition and nucleolar stress, which is the likely driver of PT-112-induced cancer organelle stresses and ICD.
PT-112 is a novel inhibitor of ribosomal biogenesis, which leads to selective immunogenic cancer cell death (ICD). PT-112's mechanism of action governs intracellular events that cause the release of damage-associated molecular patterns known to bind to dendritic cell and natural killer cell receptors, prompting an anti-cancer immune response.
Promontory Therapeutics Inc. is a privately held, clinical-stage drug development company focused on small-molecule immunotherapy in cancer. The company's lead therapeutic candidate, PT-112, has demonstrated single-agent and combination anti-cancer activity and an attractive tolerability profile across three Phase 1 studies.