Overcoming Therapy Resistance in SCLC - PROJECT SUMMARY/ABSTRACT Small cell lungcancer (SCLC) is a pulmonary neuroendocrine cancer with very poor prognosis and limited effective therapeutic options. Chemotherapy has been used for the past 30 years as for the treatment for SCLC. While most SCLCs initially respond to this treatment, nearly all relapse. Recently, immunotherapies have been introduced in SCLC treatment. While these treatments have revolutionized the treatment of non-small cell lung cancer (NSCLC), they are only effective in a very small subset of SCLCs. Thoracic radiation is recommended in the course of both limited stage (LS) and extensive stage (ES) SCLC. Radiation has been shown to induce durable responses by engaging anti-tumor immunity. However, radiation therapy while effective in some individuals, does not always convert immunologically non-responsive “cold” tumors to become immune responsive “hot”. These observations highlight the need to develop new effective treatments for SCLC. In many cancers, the loss of cell cycle checkpoints, together with oncogene activation, leads to cell survival even with high levels of replication stress (RS) and DNA damage. Cellular pathways respond to RS, to ensure that DNA is properly replicated and to prevent cells from prematurely entering mitosis. However, in most advanced solid tumors, there is an increase in a variety of errors during DNA synthesis, disruption of the DNA damage response, and mitotic catastrophe. This continuous and high degree of RS and dependence on DNA repair provides a potential cancer vulnerability and therapeutic opportunity. The vast majority of human tumors including nearly all of SCLCs are dependent on telomerase holoenzyme to bypass replicative senescence resulting from telomere shortening with each cell division and this creates a dependency. We are proposing to utilize a molecule that interferes with the function of telomerase to rapidly stop SCLC growth with minimal or no cytotoxic side effects in normal telomerase silent tissues. In our preliminary studies, we discovered that this molecule not only can kill cancer cells in culture dish, it can also activate the immune system when given intermittently to the mice. We propose to discover how this molecule sensitizes SCLCs to radiation or chemotherapy treatment (Aim 1), Induce immune responses (Aim 2), and to determine whether it can overcome resistance to existing treatments (Aim 3). For this goal, we will utilize fully immunocompetent mouse models. Therapies that activate immune system have been less toxic compared to other treatments and often provide more durable responses in patients. We hope that our studies with this molecule will generate information to develop rationally designed clinical trials which utilize combinations with minimal toxicity and maximum therapeutic efficacy in small cell lung cancer
