Neuropilin-2 Inhibitor as a Potent Therapy for Prostate Cancer Bone Metastasis
Abstract
The proposed study will address one of the FY20 PCRP Overarching Challenges, which is to “develop treatments that improve outcomes for men with lethal prostate cancer.” Bone is the most common site of metastasis for men with advanced prostate cancer. Five-year survival of these patients with bone metastasis is only 3%, and the vast majority of men diagnosis with bone-metastatic prostate cancer will die from the disease. There is no effective therapy to date that can effectively cure prostate cancer bone metastasis. Systemic chemotherapy with the taxane-based drug docetaxel (Taxotere) can be used to treat metastatic prostate cancer; however, the tumors often will become resistant after a matter of months. The reason for this quick relapse following docetaxel treatment is that the metastatic cancer cells develop ways to be resistant against the chemotherapy. Our studies for last several years suggested that a cell-surface protein called neuropilin-2 is highly found in metastatic prostate cancer cells especially when they are in bone and is responsible for their ability to resist therapy. We therefore think that blocking the function of neuropilin-2 will make the cancer cells more vulnerable against chemotherapy. Using a mouse model of prostate cancer bone metastasis, where neuropilin-2 can be removed in cancer cells and simultaneously treated them with chemotherapy, we observed a profound cancer cell killing effect in tumor-bearing mice where this combination approach was implemented. The effect is significantly more in comparison to mice that were treated either with NRP2 removal only or chemotherapy. Based on these preliminary results, we hypothesized in the current proposal that a neuropilin-2 targeting drug in combination with chemotherapy should be an effective treatment strategy for prostate cancer patients with bone metastasis. Recently, with the help of computer modeling-based screening strategy and supportive wet laboratory-based studies, we have identified a Food and Drug Administration (FDA)-approved drug, which can specifically block neuropilin-2. In this proposal, we will test the potential of this drug in the combination with chemotherapy in preclinical mouse model of prostate cancer bone metastasis. We will also study a blood-based biomarker that will can indicate high neuropilin-2 expression in metastatic bone tissues. This marker will thus help to stratify metastatic patients, who will be best suited for neuropilin-2 targeting drug therapy. Successful completion of the proposed project will eventually lead to the anti-neuropilin-2 drug as a frontline therapy for the lethal metastatic prostate cancer. Since this anti-NRP2 drug is an FDA-approved drug for other disease-specific uses, detailed information about its regarding its pharmacology, formulation, and potential toxicity to humans is known. Repurposing this drug to treat lethal prostate cancer can be done with ease. We expect within a 5-8-year time period from now, the drug can complete the necessary clinical trials and be integrated as a therapy for prostate cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110628
Entities
People
- Kaustubh Datta
Organizations
- United States Army
- University of Nebraska Medical Center