Leena Gandhi M.D., Ph.D.

Recipient of the Kate McMullen Foundation/Barbara Parisi Fund Research Grant. Funded equally by the Kate McMullen Foundation and the Barbara Parisi Fund.

Lay Description

Lung cancer is the most common cause of cancer death among both men and women in the U.S. The primary reason for shortened patient survival is the onset of metastasis, or widespread disease beyond the original cancer site. Understanding the factors that promote this process and identifying drugs that target these factors could favorably impact survival rates.

CXCR4 is a protein expressed on the surface of many types of cancer cells, including both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Increased CXCR4 protein in tumors is associated with increased interaction of tumor cells with surrounding cells, migration, metastasis, and poorer survival.

We hypothesize that inhibition of CXCR4 function will reduce or block the migration of tumor cells to form metastatic tumor deposits. In order to test this hypothesis, we will use preclinical models of both NSCLC and SCLC that recapitulate the full range of cancer progression, from primary tumor development to metastatic spread. We propose to study changes in CXCR4 and CXCL12, an extracellular protein made in potential metastatic sites that regulates CXCR4, during the course of tumor development and metastatic progression in these models. In addition, we will assess the effects of a drug that inhibits CXCR4 function, CTCE-9908 (Chemokine Therapeutics), in both metastatic and non-metastatic preclinical models to determine whether this drug can effectively reduce tumor growth or metastatic spread and improve overall survival. These experiments will form the foundation for a proposed clinical trial of this agent in patients with SCLC and hopefully pave the way for understanding how CXCR4 inhibitors may be used in patients to block disease progression.

Scientific Abstract

Lung cancer is the most common cause of cancer death among both men and women in the U.S. As the primary reason for shortened survival is the recurrence of metastatic disease, understanding the factors that promote this process and identifying targets for intervention could favorably impact survival rates.

CXCR4 is a chemokine receptor for CXCL12 (SDF-1) which has been implicated as an important contributor to metastatic progression. CXCR4 is expressed ubiquitously in SCLC and frequently in NSCLC and in both cases, has been associated with increased metastases and worsened survival. CXCR4 expression is upregulated by hypoxia-inducible factors (HIFs) expressed by tumor cells under hypoxic growth conditions. Interaction with its ligand, CXCL12, results in increased integrin expression, adhesion to stromal cells, migration, and metastasis.

We hypothesize that inhibition of CXCR4 interaction with CXCL12 will inhibit tumor-stromal cell interactions and the development of distant metastases to improve overall survival. We propose to evaluate CXCR4 inhibition in endogenous preclinical models of lung cancer progression carrying conditionally activated oncogenic mutations that have been previously generated and characterized: 1) a metastatic SCLC model carrying inactivated Rb1 and p53, 2) a metastatic NSCLC model carrying inactivated Lkb1 and p53 with activated Kras and 3) a NSCLC model carrying activated HIF2 and Kras that results in bulky tumors with extensive tumor-stromal interaction. Each will be assessed for CXCR4 and CXCL12 expression and circulating CXCL12 through the course of development to determine the relationship between these proteins and cancer progression. In addition, CTCE-9908 (Chemokine Therapeutics), a small molecule CXCR4 antagonist, will be used in treatment trials to assess the effect of CXCR4 inhibition on primary tumor growth, metastatic progression and overall survival. These experiments will form the foundation for a proposed clinical trial of this agent in patients with SCLC and hopefully pave the way for understanding how these inhibitors may be used in patients to block disease progression.