Supported by Bristol-Myers Squibb through the Robin Roberts Cancer Thrivership Fund
Cancer survivors often continue to have certain side effects of anti-cancer drugs long after treatment has ended. Their hands and feet may feel numb, or they may feel unpleasant sensations in their hands and feet like burning. The simple touch of clothing or holding a cold can of soda may feel painful. Pin prick or paper cuts may hurt more than expected. These abnormal sensations are called chemotherapy-induced peripheral neuropathies (CIPN). They can seriously diminish the quality of life, and interfere with self-care and activities of daily living. Sixty-eight percent of patients report these abnormal sensations when asked 30 days after the end of anti-cancer treatment. Although the abnormal feelings may decrease over time, they can persist for months to years in as many as 30% of cancer survivors. Advances in diagnosis and treatment of cancer have increased the number of survivors to nearly 14.5 million. Of these, up to 4.5 million may continue to suffer CIPN long after their treatment has ended. There are no effective drugs for these survivors. We recently discovered that NIAGEN®, a type of vitamin B3 that increases levels of NAD+, can prevent abnormal sensations in a rat model of CIPN. Importantly, it can also reverse CIPN that persists after the last dose of paclitaxel. The goal of this study is to translate these laboratory findings to the clinic and the patient. Here, we will determine whether daily treatment with NIAGEN can relieve residual persistent CIPN in cancer survivors.
Funded by Papa John’s International
Obesity, defined by body-mass index over 30.0, influences more than 30% of American adults and is associated with increased incidence and/or bad prognosis of various cancers including esophagus, pancreas, colon and rectum, breast, and endometrium etc. Obesity contributes directly to the 34,000 new cancer cases in men (4% of all cancer) and 50,500 in women (7% of all cancer) in 2007, based on the NCI Surveillance, Epidemiology, and End Results (SEER) data. In addition, obesity increases the risk for many different types of cancer including breast cancer and decreases patient survival and is associated with bad outcome. Obesity always correlates with increased basal level inflammation. It is unknown, however, if obesity-associated inflammation promotes cancer progression and what is the molecular sensor for obese tumor microenvironment. Here we found that sterile inflammation–a type of inflammation without clear infections and activated by danger signals released by tissue damage–in the obese tumor microenvironment, led to Nlrc4-inflammasome activation. We found that interleukin-1beta is the major downstream mediator for Nlrc4-inflammasome activation that provides a pro-inflammatory signal to be required for tumor growth in obese mice, but not in normal-weight ones, by promoting angiogenesis in obese tumors. Our goals are to understand how obesity contributes to cancer progression, and to develop treatments to obese cancer patients.
The proposed study has ground-breaking impacts on basic cancer biology and cancer therapy to obese cancer patients. For cancer biology, we identified the molecular sensor in obese tumor microenvironment and aim to detect ‘danger signal’ from obese tumors, which, in turn, promotes cancer progression via activation of interleukin-1beta. For cancer therapy, given that ~30% Americans are obese and many cancer types are influenced by obesity, our study will have big impact on cancer patients. Anakinra is a known decoy receptor to inhibit interleukin-1 receptor-mediated signaling and has been improved drug to treat rheumatic arthritis. Caspase-1 (the major enzyme for inflammasome-mediated interleukin-1beta activation) inhibitors have been in several clinical trials. In addition, we found that metformin reduces obesity-associated tumor growth. These drugs can be easily and quickly adapted for treating obese cancer patients, together with current standard care for cancer patients.