Small-Molecule Inhibitor Targeting RPN13 and Chemoresistance
Abstract
For 2019, there will be an estimated 22,530 cases and 13,980 deaths from ovarian cancer, and this represents 5% of all cancer deaths among women. Unfortunately, ovarian cancer remains the most lethal gynecologic cancer, with overall 5- and 10-year survival rates of 44% and 34% respectively, which have seen little improvement despite aggressive surgery and chemotherapy regimens. Our overall goal is to reduce the morbidity and mortality caused by epithelial ovarian carcinoma by developing our new targeted drug to enhance the efficacy of current therapeutic approaches, notably platinum-based chemotherapy. High-grade ovarian carcinoma is the most common and lethal type of ovarian cancer and therefore is the focus of our proposal. Standard-of-care treatment for high-grade ovarian carcinoma includes total abdominal hysterectomy and aggressive surgical removal of the bulk of tumor mass by a gynecologic oncologist, followed by multiple rounds of platinum-based chemotherapy with paclitaxel. This aggressive approach is typically effective in providing an extended remission, but it also has significant side effects, and eventually most patients succumb to their ovarian cancer as resistance to platinum-based chemotherapy emerges. There remains an urgent unmet medical need for new combination treatment approaches with greater efficacy and less toxicity to overcome this drug resistant disease. RPN13 is cellular protein that has emerged as a promising new therapeutic target for ovarian cancer treatment. We have developed a novel series of small molecules as promising cancer drugs and demonstrated that the lead compounds act by chemically reacting with RPN13. Treatment with our first-generation RPN13 inhibitor drug, RA190, directly and selectively killed ovarian cancer cells in laboratory cultures and in mice. In addition, treatment of mouse ovarian cancer models with RA190 caused their immune systems to recognize and attack the tumors. Our candidate RPN13 inhibitor RA190 works by selectively triggering a toxic buildup of protein in the cancer cells. Certain cancer cells are particularly sensitive to RA190, whereas others were more resistant. Here we are studying whether this range in sensitivity reflects a difference of glutathione metabolism, a well-known drug-resistance mechanism. The innovation in our proposal is the addition of a chloroacetamide-based warhead into the RA190 drug structure because this has the potential to neutralize glutathione metabolism. Our early studies suggest that this new drug (RA371) is more therapeutically potent, and we expect it to be more broadly acting against otherwise drug-resistant ovarian cancers. Since it is the critical first-line chemotherapeutic agent used to treat ovarian cancer, our focus here is preventing/overcoming resistance to cisplatin by combination treatment with our novel RPN13 inhibitor, RA371, which comprises our first-generation drug RA190 that has an added chloroacetamide warhead. Importantly, this glutathione metabolism is a common mechanism of drug resistance that can also limit the effectiveness of the platinum-based chemotherapy currently used to treat ovarian cancer. By inactivating glutathione metabolism with RA371, we also expect to increase the direct antitumor therapeutic activity of platinum-based chemotherapy and that the drug cocktail will enhance the body’s immune response against the cancer by triggering an immunogenic cell death. In this situation, it may also be possible to reduce significant side effects of platinum-based chemotherapy by using lower doses in combination with RA371. In the short term, our studies will first provide a more detailed understanding of how our RPN13 inhibitors kill cancer cells and whether the cancers try to resist its effect using their glutathione metabolism. We will show how a second-generation version, RA371, overcomes the glutathione resistance mechanism and, after determining the appropriate dosing and
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210364
Entities
People
- Richard Roden
Organizations
- Johns Hopkins University
- United States Army