Research

Radiation sensitizing chemotherapy has shown promise in the clinic for cancer treatment. However, toxic side effects limit higher doses of systemically administered chemotherapy. In this project, radiation-sensitizing chemotherapy is being delivered specifically to cancer using antibody-drug conjugates (ADCs). We discovered a new cancer antigen that carries the ADCs specifically into cancer cells. Once the ADC is within the cell, the radiation sensitizing drug is released and enhances the efficacy of therapy. Therefore, this approach delivers radiosensitizing drugs specifically to cancer each day compared to the current once-weekly administration of systemic chemotherapy. This new paradigm of guided delivery of the ADCs to tumors treated with radiation therapy will lead to clinical trials.

Non-small cell lung cancer (NSCLC) ranks among the highest cancer-related mortalities world-wide. Molecular targeted therapy is a growing topic of investigation to improve therapeutic efficacy for NSCLC. A few targeted therapies that exploit aberrant protein expression profiles have been approved for NSCLC. However, the marginal percentage of cancers with improved efficacy observed with these therapeutic approaches highlights the need for discovery of additional molecular targets. We propose targeting of the scaffold protein TIP1 that is a novel target for lung cancer as identified by analysis of the cancer genome atlas datasets and NSCLC tumor tissue microarrays. The functional domain of TIP1 (PDZ domain) caps the C-terminus of many different cellular proteins that regulate important cellular functions. Knocking down TIP1 revealed that it plays an important role in cell signaling, cancer development, and progression making it an attractive target for anticancer therapeutics. Comparing antibodies targeting different epitopes of TIP1, it was found that antibodies against the PDZ domain of TIP1 were most effective in inducing direct cytotoxicity of lung cancer cells but not normal cells. Anti-PDZ/TIP1 antibodies injected into mice bearing lung cancer bind specifically to cancer cells and substantially enhance tumor control. Quantitative mass spectrometry identified Midkine (MDK) as a putative protein that modulates this cytotoxicity by anti-PDZ/TIP1 antibodies. Additional studies suggested that the β-catenin/Wnt signaling may be involved in this up-regulation of MDK after blocking of TIP1. Together, these studies led to the central hypothesis that MDK is upregulated by the anti-PDZ/TIP1 antibody via the β-catenin/Wnt signaling pathway, which subsequently modulates downstream cell death mechanisms. In this project, we will elucidate the mechanisms of induction of MDK following blockade of the PDZ domain of TIP1. In addition, we will evaluate the efficacy of blocking TIP1 function while simultaneously blocking MDK function in mouse models of NSCLC.