Testicular cancer is the most common carcinoma of adolescents and young males and the most common carcinoma affecting males in the military who are of active duty service age. After age 35 the incidence of testicular cancer drops dramatically. Approximately 80% of patients are cured of their disease with conventional chemotherapy, but this therapy is very toxic to the patient. Acute toxicities include suppression of white blood cells so patients are prone to infection and severe nausea. Long-term and lifelong toxicities include infertility, decreased lung and kidney function, pain and tingling in extremities, hearing loss, a higher risk of cardiovascular and heart disease, and psychological and social distress. Because patients can be in their teens they can live with these side effects for 60 years or more.

Also, testicular cancer survivors have an increased risk of getting other kinds of aggressive cancers later in life because the drugs to treat testicular cancer can themselves cause mutations throughout the body leading eventually to malignancies. In addition, there are a subset of patients that do not respond to the toxic therapy and, also, patients who do respond but then relapse. These patients have very poor prognosis. There is an immediate clinical need for new, innovative strategies to treat these cases, which are nearly universally fatal.

"Targeted therapy" is a relatively new concept in oncology. Instead of using non-specific cytotoxic drugs, drug are being designed that "target" unique features of a particular type of cancer. An example is tamoxifen for breast cancers that express the estrogen receptor. So far, no targeted therapies are available for testicular cancer. However, we have made the discovery that testicular cancers express very high levels of an enzyme called DNMT3B compared to other kinds of solid tumors like breast, lung, and colon tumors. Further, a drug called 5-aza that inhibits DNMT3B and already is being used in humans to treat a rare form of preleukemia, can potently inhibit the growth and survival of testicular cancer cells at very low doses, doses so low that other types of cancer and normal cells are not affected. Particularly notable, we found this was true even for testicular cancer cells that are resistant to the current cytotoxic therapy. We have also performed experiments that strongly suggest that the hypersensitivity of testicular cancers to 5-aza is due to the high levels of DNMT3B.

The objectives of this proposal are: (1) To find out how and why 5-aza is suppressing the growth of testicular cancer cells so efficiently compared to other cancers; (2) To formally validate that the sensitivity of testicular cancers to 5-aza is indeed due to the high levels of DNMT3B; and (3) To see if tumor samples taken directly from patients also express high levels of DNMT3B and whether the high expression corresponds to whether the patient is resistant or sensitive to cytotoxic therapy.

Achieving these objectives will provide compelling rationale to perform a clinical trial to see if low dose 5-aza can better treat testicular cancer in a way that is less toxic and has less side effects than current therapy. Further, this type of therapy could provide hope for those testicular patients that have failed all available cytotoxic therapies. Finally, testicular cancer has been an important model disease for oncologists to test cancer drugs. Indeed, many of the most commonly used therapeutic agents in cancer were first shown to be used successfully in testicular cancer patients. The concept of combination therapy was also validated in testicular cancer patients before being applied to patients with other kinds of cancer. Thus, lessons learned from this study and follow-up studies could directly impact therapy of other human cancers.