Adenocarcinoma

The overarching goal of the project is to develop a new technology for accurate and cost-effective lung cancer screening in current/former smokers. Lung cancer is curable if detected early. However, there are no robust screening techniques with options such as CT scans fraught with cost, harms, and a high false positive rate. Dr. Backman and his group hope to transform the clinical practice of lung cancer screening by exploiting field carcinogenesis, the concept that the genetic/environmental milieu that results in lung tumor impacts upon the entire aerodigestive mucosa including the buccal mucosa, which was referred to as a “molecular mirror” of lung carcinogenesis.

Their data show that the alteration of nanoscale architecture of buccal cells is exquisitely sensitive to lung field carcinogenesis and may serve as a robust biomarker for lung cancer. These nanoarchitectural changes can be detected in a practical and highly accurate fashion via a new technology, partial wave spectroscopic (PWS) microscopy (‘nanocytology’).

In the proposed study, they will conduct a blinded validation case-control trial to determine the sensitivity and specificity of buccal nanocytology for lung cancer. They will evaluate the ability of the test to identify patients who have lung cancer and how many patients with lung cancer would be missed using this technique. They will perform a subgroup analysis for Stage I lung cancers. They will assess the potential confounding effects of smoking frequency and time of cessation and other aerodigestive malignancies.

This project will provide the requisite data for the future definitive multicenter validation trial followed by FDA submission.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-associated deaths worldwide. Given the limited effectiveness of current treatments, there is a significant need to identify new driver genes that participate in lung cancer pathogenesis. Dr. O’Donnell and her group identified PROTOCADHERIN 7 (PCDH7) in a functional screen for genes that promote transformation of human bronchial epithelial cells (HBECs). This is of interest because PCDH7 encodes a poorly characterized cell surface receptor that is frequently overexpressed in NSCLC and high expression strongly associates with poor survival of NSCLC patients. Moreover, the presence of PCDH7 on the cell surface highlights the potential of this molecule as a novel target for future therapeutics.

They demonstrated that 1) enforced expression of PCDH7 is sufficient to promote transformation of HBECs, 2) PCDH7 cooperates with oncogenic KRAS to promote tumorigenesis, and 3) PCDH7 potently enhances KRAS-mediated activation of the ERK1/2 pathway. They will elucidate the role of this lung cancer driver by testing the following central hypothesis: Overexpression of PCDH7 initiates a signal transduction cascade that potentiates KRAS-induced MAPK-ERK signaling to promote lung tumorigenesis. In Aim 1, they will correlate PCDH7 immunoexpression with clinical features of resected NSCLCs. In Aim 2, they will elucidate the mechanisms through which PCDH7 potentiates MAPK signaling and tumorigenesis. In Aim 3, they will develop and test the therapeutic efficacy of PCDH7 blocking antibodies in patient-derived xenografts.

These experiments will yield insights into the mechanisms of PCDH7-mediated transformation and reveal new opportunities to pursue this cell-surface receptor as a therapeutic target in NSCLC.

KRAS mutations activate signaling from downstream effector proteins and are though to be required for tumor formation. Exactly how effector signaling is activated, however, is not fully understood. In addition, whether tumors harboring KRAS mutations depend on this oncogene for growth is unclear.

Dr. Lito and his group will dissect the phenotype of KRAS-mutant lung cancer by using a novel allosteric inhibitor that selectively targets KRAS G12C. They will first utilize biochemical assays in order to determine the mechanism of action of this inhibitor. An emphasis will be placed on evaluating how feedback pathways modulate this process, since this is likely to identify factors that may be used as biomarkers of response to treatment.

They will then determine which effector pathways drive the phenotype of KRAS G12C mutant lung cancer, and whether these exhibit adaptation (or reactivation) over time. If so, they will next explore combination-based interventions in order to establish the most effective antiproliferative strategy.

Finally, they will utilize novel patient-derived xenograft and cell line models, established from patients with lung cancer treated at MSKCC, in order to determine if KRAS G12C mutant lung cancers depend on this oncoprotein for growth. These models will also be used to test the most effective combination strategies determined above, as well as to test the potential benefit of intermittent administration schemes designed to best target tumor adaptation to this novel class of inhibitors.

The grand objective of this project is to establish a mutant KRAS-directed therapy for patients with lung cancer.