PMR-116, a Novel Inhibitor of Ribosome Biogenesis with Antitumor Activity in Preclinical Models of Prostate Cancer
Abstract
One in seven men will be diagnosed with prostate cancer (PC) in their lifetime, and PC related deaths are above 20,000 per year in the USA. Despite approaches such as surgical removal of the prostate, radiation therapy, and androgen deprivation, many patients still develop advanced cancers, which inevitably acquire resistance to very low (referred to as castrate) levels of testosterone; this most aggressive state is referred to as castration-resistant prostate cancer (CRPC). While new anti-androgen treatment regimens have delayed the onset of metastatic CRPC (mCRPC), it remains a lethal condition with limited treatment options, which at best only provide short-term disease control. By using functional imaging with positron emission tomography (PET), it is clear that PC has significant tumor heterogeneity in late stage disease and metastatic deposits are likely to contribute to the disease’s resistance to standard therapies. In response to this resistance, there has been an increasing number of PC patients, emerging with the aggressive form of PC, CRPC with neuroendocrine differentiation features (NEPC). The prognosis of NEPC patients is extremely poor, owing to resistance to conventional therapies. Consequently, new therapeutic strategies to target CRPC in general and NEPC in particular are critical to improve outcomes for PC patients, and the use of combination therapies needs to be considered to better target tumor heterogeneity. In this project, we will determine whether a novel second-generation therapy targeting the tumor’s cellular machinery responsible for making proteins (called ribosomes) alone or in combination with a second novel therapy targeting the tumor’s genetic material via selective delivery of a radioactive cargo specifically to tumor cells will be efficacious in PC, especially the aggressive forms CRPC and NEPC. The principal investigators (PIs) and co- investigators (CoIs) have taken their class of drugs, which targets the making of ribosomes, to a phase I clinical trial, and it has been shown to be efficacious. The research team have taken their novel system of targeting radioactive material to the cancer cells also successfully to the clinic. Based on our strong clinical and preclinical data, our international expertise in our respective fields, we formulated the hypothesis that the second- generation ribosome targeting therapy either alone or in combination with the radioactive cargo therapy will eradicate tumor cells more effectively that current therapy regimens. As our approach is independent from the targets of current standard of care in PC, it could be used in combination for patients with CRPC. Overall, this research project will address the overarching challenge of developing treatments that improve outcomes for men with lethal prostate cancer. Our preliminary results in preclinical models suggest that our new compound, PMR-116, has the potential to suppress tumor growth in some of the most aggressive subtypes of PC, including NEPC. To perform this project, we have assembled a unique, multidisciplinary, internationally competitive team of investigators with proven track record of conducting clinical trials in PC. We therefore have the capabilities and experience to bring a new drug to clinical trial for men with lethal PC. We expect that, if promising results are obtained from this translational research project, men with metastatic CRPC and NEPC could participate in a phase II trial of PMR-116 (phase I trial commenced in January 2021). We consider that improving disease-specific outcome for men with PC should also come with increased quality of life, and it is noteworthy that few side effects were observed in both clinical trials of first-generation ribosome targeting and prostate-specific radioactive cargo therapies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211039
Entities
People
- Ross D. Hannan
Organizations
- Australian National University
- United States Army