Lung cancer causes more deaths than any other human malignancy. One of several challenges in the treatment of lung cancer is the issue of tumor heterogeneity, that is, any single patient with lung cancer might have a tumor that is radically different in its genetics and molecular features from another patient with lung cancer. This issue leads to several challenges for oncologists when they seek to offer the most effective medicine to a patient. Indeed, many of the cytotoxic chemotherapy agents that are currently used to treat lung cancer are poisonous substances that damage any cell that is actively growing, which leads to several major side effects of diminishing normal blood counts and hair loss. Importantly, the current arsenal of chemotherapy agents do not exploit the major molecular features that are unique to a patient’s tumor. Hence, for most lung cancers, we lack any form of “personalized medicine” that would be highly effective and safe for a specific individual.

These issues are particularly relevant in a subtype of lung cancer known as small-cell lung cancer (SCLC), which is the most deadly form of lung cancer. SCLC is well known in the oncology field for its rapid growth and its strong propensity for metastatic spread prior to being diagnosed. Important efforts in the 1970s led to the development of chemotherapy drug regimens for SCLC that can lead to profound, but temporary, elimination of tumor tissue. However, for nearly all SCLC patients, the tumor will evolve and return as a chemotherapy-resistant disease within a few months. With the latest medicines we have available in the clinic, there is only a 6% chance that a patient with SCLC will be alive 5 years after their diagnosis.

In my research laboratory in Cold Spring Harbor, New York, we are pursuing a new paradigm in the treatment of SCLC. Over the past couple of years, we have made an unexpected discovery, in which SCLC is not one single disease, but is in fact two different diseases. Remarkably, this observation has escaped the notice of pathologists in community hospitals who diagnose SCLC, since these two flavors of SCLC look very similar to one another when inspecting tumor tissue under the microscope. However, our detailed molecular analysis, which includes CRISPR-based genome editing, has revealed startling differences between these tumors. The genetic material in these tumors, which we often refer to as chromatin, is in a radically different configuration in the two subtypes of SCLC. In addition, the two forms of SCLC are addicted to different proteins. In fact, our observations lead us to believe these two types of SCLC tumors are in fact derived from different cells in the normal lung. In approximately 80% of SCLC tumors, we believe that cigarette smoking led to the accumulation of DNA mutations in a cell type known as a neuroendocrine cell. In addition, we have learned that about 20% of SCLC happens because of smoking-induced mutations in a cell type of known as a tuft cell. This new knowledge is leading us to rethink our current definition of this disease and now motivates us to use this knowledge to devise personalized therapies.

The 2-year research plan outlined in this application represents a key step in the development of personalized therapies for SCLC. We will study the unique protein addictions that are present in these two flavors of SCLC. One can think of these addictions as an “Achilles Heel” of each tumor, which is intimately related to the biological differences that exist between normal neuroendocrine cells and normal tuft cells. We will develop new drugs that can exploit the vulnerabilities in these different tumors and devise rational drug cocktails that lead to the most effective anti-tumor response while also sparing normal tissues. Overall, we believe our research proposal will lead to important new knowledge about how we treat SCLC in the future, and we anticipate our findings reaching a clinically relevant outcome within 5 years. In addition, since population-based studies have found a higher incidence of lung cancer and lower overall survival among military men and women when compared to civilian populations, this research will also have a significant impact on military Service members, Veterans, and their families.