The American Cancer Society estimates that over 80,000 individuals will be diagnosed with bladder cancer this year. Unfortunately, in the same year, it is estimated that over 15,000 deaths will be attributed to the same disease. Statistics indicate that bladder cancer is more prevalent in men and that smoking is the biggest risk factor. Other risk factors include exposure to chemicals involved in painting, leather work, metal work, mining, and plastics. Although rates have minimally decreased in the last year, advanced bladder cancer is extremely difficult to control. Advanced bladder cancer results in difficulty urinating, pain, severe weakness and fatigue, weight loss, and fever/chills. If the cancer has traveled to other sites of the body, patients may experience swollen feet, shortness of breath, or jaundice. Unfortunately, there is no cure and treatments tend to be used in combination to maximize antitumor efficacy.
Patients with bladder cancer are commonly prescribed chemotherapy, which eliminates cancer cells by dysregulating the intracellular mechanisms. This treatment has been effective for decades; however, it has off-target effects and results in toxicity. Consequently, scientists have developed targeted therapies to overcome these chemotherapeutic side effects. One form of cancer treatment that has significantly improved clinical outcome overall is referred to as immunotherapy. In the context of cancer, immune cells become skewed to promote tumor growth. Immunotherapy redirects these skewed immune cells so that they regain their ability to recognize and target the tumor.
While therapies have improved, efficacy is limited based on tumor type and stage of disease. A recent article in Nature Communications, by Dr. Sangeeta Goswami and others, demonstrated that mutational burden in advanced bladder cancer cells can predict chemotherapy resistance and immunotherapeutic efficacy. Goswami is an Associate Professor in the Department of Genitourinary Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson, Houston, Texas. Her work focuses on molecular modifiers in cancer and how to better elicit anti-tumor immunity through tumor biology. Specifically, Goswami and her group target the genetic makeup of cancer to sensitize tumors to immunotherapy.
Researchers studied the KDM6A gene, which is mutated in about 30% of all advanced bladder cancer. The gene is responsible for turning genes associated with cell development and function on and off in cancer cells. With the use of mouse models and human patient samples, the team discovered that tumors with loss of KDM6A were resistant to chemotherapy. However, the same cells were sensitized to immunotherapy. In the study, loss of KDM6A in cancer cells generated a DNA structure that maintained genes, which drove resistance to chemotherapy. Similarly, the DNA structure was unable to properly repair itself, which led to sensitivity to immunotherapy. KDM6A loss also altered tumor metabolism and slowed down tumor consumption of nutrients. The delay in metabolism also helped immune cells better target the cancer due to its weakened ability to maintain energy production.
This is a major discovery because it allows physicians to analyze the tumor and better prescribe treatment to patients that will most likely benefit from it. Research suggests that KDM6A could work as a diagnostic marker and predict treatment efficacy. Goswami hopes this will provide insight into developing a therapeutic strategy for a wide range of cancer types. Overall, this work provides a biological understanding of KDM6A’s role in cancer and how it can be used to help patients.
Article, Nature Communications, Sangeeta Goswami, The University of Texas MD Anderson
