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Project

Dissecting the Role of APOBEC3 Mutagenic Proteins as Drivers of Genomic Instability and Chemotherapy Resistance in Urothelial Carcinoma

Funder: Congressionally Directed Medical Research Programs

Funding period
USD 610 K
Funding amount
Abstract
PUBLIC ABSTRACT

The most common type of bladder cancer is urothelial carcinoma. It is the fifth most common cancer in the United States. Each year there are 77,000 new diagnoses of urothelial carcinoma. It kills 16,000 patients in the United States every year. Among Veterans, it is the fourth most common cancer. Urothelial carcinoma often penetrates the muscle layer of the bladder eventually spreading beyond the bladder to other organs, that is, becomes metastatic. Metastatic urothelial cancer has no uniformly curative treatment at present. The standard treatment, chemotherapy including a drug called cisplatin, nearly always stops working because bladder cancer cells evolve, developing resistance to chemotherapy. There is currently only one drug approved by the Food and Drug Administration to treat chemotherapy-resistant metastatic urothelial cancer. However, only one-third of patients respond to this new therapy. Progress in bladder cancer research has been very slow over the last three decades. This is mainly because we do not understand the changes in urothelial cancer cells that lead to drug resistance. As a cancer physician (medical oncologist) and a physician-scientist, it is the Principal Investigator’s career goal to contribute to solving this problem.



It is likely that sudden and permanent changes in the genetic makeup of bladder cancer cells enable them to mutate and become resistant to cisplatin-based chemotherapy. From previous studies, we know that a family of proteins called the APOBEC3 proteins introduces “typos” (mutations) into the genetic material of each cancer cell. We detected in our preliminary data that such mutations caused by these proteins are increased in chemotherapy-resistant tumors. We postulate that these proteins play a major role in promoting genetic instability in urothelial cancer cells. This genomic instability yields drug resistance. The goal of this project is to determine the mechanisms by which APOBEC3 proteins cause mutations that lead to chemotherapy-resistant urothelial carcinoma. By comparing the genetic makeup of the first (primary) untreated tumors and matched chemotherapy-resistant tumors from individual patients, coupled with laboratory experiments to produce mutations caused by APOBEC3 proteins, the Principal Investigator will be able to uncover the key steps in the development of these mutations that lead to the emergence of chemotherapy resistance.



The Department of Defense Career Development Award will be critical in advancing the Principal Investigator’s career goals to improve outcomes for patients with bladder cancer. The Principal Investigator is a medical oncologist at Weill-Cornell Medicine who dedicates his clinical practice to treating bladder cancer patients. He is a physician-scientist who focuses his research on understanding the genetic changes that lead to genomic-instability-related drug resistance. This combination of roles makes him uniquely well positioned to translate findings from this research into new therapeutic advances for bladder cancer patients. He has created a career development plan to provide the additional education and mentoring he needs to become a truly independent and original researcher. He will collaborate with other scientists to accelerate new discoveries and translate them into benefits to patients. By performing this research, working with his world-class team of mentors and collaborators, the Principal Investigator will become an independent expert in this area of bladder cancer research. This will enable him to make significant advances towards addressing the clinical challenge of drug resistance in bladder cancer.



In the near term, the research will have several important clinical applications for the majority of patients with advanced bladder cancer. We expect that it will lead to the identification of the genetic changes that predict which patients will develop resistance to chemotherapy. This will allow physicians treating Service members, Veterans and their families to apply precision medicine approaches. It will permit clinicians to tailor treatments to the individual biology of different patients’ cancers. In the longer term, this work will also pave the way for the development of new treatments. For example, we can expect drugs that target the APOBEC3 proteins to prevent them from inducing the harmful mutations underlying drug-resistance. We also know that APOBEC3 proteins induce mutations in other cancers that are usually treated with DNA-damaging chemotherapy, such as breast and cervical cancers. Understanding the interaction between the mutations caused by APOBEC3 proteins and chemotherapy should deliver findings that can be extended to patients suffering from other types of cancer. This proposal addresses the important clinical problem of chemotherapy resistance in urothelial bladder cancer. This problem is faced by the many active duty Service members, their families, Veterans, and other military beneficiaries who face urothelial bladder cancer. We expect that the results of this research will open the door to new, more precise and less toxic treatment approaches for patients with advanced urothelial bladder cancer.
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System

Categories
  • FOR (ANZSRC)

    1112 Oncology and Carcinogenesis

  • RCDC

    Biotechnology

  • RCDC

    Human Genome

  • RCDC

    Cancer

  • RCDC

    Clinical Research

  • RCDC

    Genetics

  • RCDC

    Urologic Diseases

  • HRCS HC

    Cancer

  • HRCS RAC

    2.1 Biological and endogenous factors

  • HRCS RAC

    6.1 Pharmaceuticals

  • Health Research Areas

    Biomedical

  • Broad Research Areas

    Basic Science