Overcoming Therapeutic Resistance in Lung Cancer Using Novel Combination Therapies

Lay Abstract Lung cancer is a deadly disease, and unfortunately is twice as prevalent in Kentucky than anywhere else in the country. My laboratory focuses on finding new treatments, including drug combinations that can target specific types of lung cancer. In this proposal, we will perform the preclinical studies needed to open clinical trials. We are targeting two types of lung cancer in this proposal. One type of tumor is EGFR-mutated, which are more common in non-smokers and young women than other lung cancers. Although patients initially respond well to the standard treatment, the tumors inevitably recur. We propose to add another medication to the first treatment to delay or reverse recurrence. The other type of lung tumors we will target are advanced stage PI3K-mutated tumors that have not responded to current treatments. Again, we will combine two drugs to treat this type of cancer. Our initial data suggest that these drug combinations work well together to kill cancer cells. We are excited to perform the remaining tests to have the confidence to move forward into clinical trials. Our proposed research may provide additional “arrows in the quiver” of oncologist that lung cancer patients need. These arrows provide hope that when a patient’s current therapy almost inevitably stops working, there will be other options. In addition, the drugs we are proposing to research are already FDA-approved or in late- stage trials, and orally bioavailable. Because of this property of oral bioavailability, these drugs have a tablet form. From a patient’s perspective, taking tablets twice daily is preferable to traveling to a cancer center to receive drug infusions. Although we cannot say whether either of these drug combinations will be so effective that they become standard-of-care, only the preclinical testing we propose will uncover this possibility. Our lab is an expert in the biology of these drugs, so we are well-positioned to do this work. Finally, uncovering the mechanisms through which the drugs synergize may suggest additional treatment strategies to explore.