Releasing the Full Potential of DNA Repair Inhibition in Prostate Cancer
Abstract
Our proposal directly addresses the FY21 PCRP Overarching Challenge to develop treatments that improve outcomes for men with lethal prostate cancer (PC), which fall into the category of high-risk, very high-risk, and metastatic. This patient population suffers from low survival and limited treatment options, to which all patients will eventually develop resistance. New treatment options, such as radionuclide therapy and DNA repair inhibition have recently become available or are expected to become available soon after the completion of pivotal phase 3 clinical studies. These treatments have shown promising results in clinical trials in their respective eligible patient population. However, it is hypothesized that patients could benefit to a much larger extent if these two novel treatments were combined. Both therapies attack the DNA of tumor cells by either introducing damage through radiation or by inhibiting the repair of DNA damage. Therefore, combining these two treatments could produce a synergistic effects that would elicit a much stronger response than either treatment alone. Unfortunately, there is a substantial risk, supported by early clinical data, of strongly increased toxicity and side effects from combining DNA repair inhibition with radiation. One of the main causes of toxicity from systemic therapy is a lack of tumor specificity. As a result, drugs can accumulate in cancer and normal tissues and can produce toxic effects in critical organs. Furthermore, combination therapy can produce overlapping toxicities that essentially render them unsuitable for clinical use. We hypothesize that minimizing passive accumulation of DNA repair inhibitors in normal cells will lead to better safety at higher drug concentrations and enable synergistic anti-tumor effects of the therapies in prostate tumors. Specifically, our approach is based on delivering the DNA repair inhibiting molecules only to prostate cancer cells, while protecting non-cancerous cells from their pharmacological effects. We have developed the first targeted DNA repair inhibiting molecules and showed selective accumulation in prostate cancer cells that express the tumor biomarker prostate specific membrane antigen (PSMA), which is present in the majority of high-risk and metastatic prostate cancers. In this proposal, we will optimize treatment using different, clinically relevant prostate cancer models using our targeted DNA repair inhibitors in combination with radioligand therapy. We will examine the effectiveness of our approach compared to the respective monotherapies and using conventional, non-prostate cancer targeted DNA repair inhibitors and have assembled a highly qualified investigative team to accomplish our aims. The potential of our research to produce strong clinical impact is largely driven by the selection of a combination therapy approach where the monotherapies are either already clinically approved or are expected to be approved soon. Thus, our approach is ideally positioned for accelerated clinical translation. We expect to identify at least one drug candidate in our project that could advance to human studies, and we have the appropriate infrastructure and team to lead such translational efforts. If effective, our strategy could produce higher response rates, more durable responses, and prolonged survival of men with lethal prostate cancer. Successful completion of our aims could also allow near-term expansion of our innovative drug design to other combination therapies and targets, which could benefit additional subpopulation of prostate cancer patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211088
Entities
People
- Susanne Kossatz
Organizations
- Technische Universität Ilmenau
- United States Army