Targeting chemokine receptor CXCR7
Cancer is the second leading cause of death in the US and afflicts over 13 million Americans. With approximately 1,600,000 new cancer diagnoses anticipated in 2013, it is clear that cancer imposes an immense burden on public health. This proposal focuses on the development of novel therapeutic agents to selectively target and destroy leukemia, glioblastoma multiforme (GBM), and breast cancer cells, as well as tumor-associated blood vessels, and thus has the potential to substantially improve public health.
CXCR7 is an atypical chemokine receptor that plays a critical role in guiding progenitor cell migration during embryo- and organo-genesis. Following fetal development and birth, however, expression of CXCR7 protein is difficult to detect on cells or tissues, except in the context of cancer. Expression of CXCR7 is regulated by hypoxia-inducible factor 1, which is commonly induced in the low oxygen environment of solid tumors. In normal adult human tissue, CXCR7 RNA and protein is expressed in the kidney and brain, although in neurons the protein is found intracellular and not on the cell surface (the cellular localization of CXCR7 protein in parenchymal kidney cells or renal multipotent progenitor cells is not known). In the context of cancer, CXCR7 RNA and protein are expressed in leukemia/lymphoma cells, GBM, breast cancer (primary invasive ductal carcinoma), lung cancer, and solid tumor-associated blood vessels. CXCR7 protein alone is also detected in rhabdomyosarcoma and cervix squamous cell carcinoma. CXCR7 RNA alone is also expressed in pituitary adenomas, renal carcinoma, pancreatic adenocarcinoma, and oral squamous cell carcinoma. CXCR7 surface protein is largely restricted to cancer cells or tumor-associated vessels and is thus a suitable selective target for therapeutic intervention.
Monoclonal antibody-based cancer immunotherapy has emerged as a powerful and precise modality to effectively target and inhibit tumor cell growth and survival. Unconjugated mAb use a variety of mechanisms to kill tumor cells, including antibody-dependent cellular cytotoxicity (ADCC) mediated by natural killer (NK) cells and other immune effectors, or complement-dependent cytotoxicity (CDC). Receptor-targeted antibodies can also block ligand binding, or elicit receptor internalization, thus decreasing responsiveness of tumor cells to extracellular survival and proliferative signals. Campath, Avastin, Erbitux, Rituxan, and Herceptin are examples of approved unconjugated mAb-based immunotherapies (see Table).
Cytotoxic bacterial toxins such as PE38, a 38-kDa truncated derivative of Pseudomonas aeruginosa exotoxin A, are also used as warheads conjugated to mAbs for immunotherapy. This strategy relies on receptor/payload internalization, as PE38 functions to inhibit translation and is only active inside the cell. PE38-conjugated immunotoxins do not require specialized conjugation or handling procedures like those required for radioactive- or chemical-toxin-based immunotherapies, and do not require an intact immune system for in vivo efficacy like many unconjugated mAbs.
Another promising immunotherapy approach based on mAbs is bispecific T-cell engagers (BiTE). These are engineered tethered divalent proteins in which one mAb fragment variable (Fv) region binds to a T cell (typically targeting CD3) and the other Fv region binds to a tumor specific antigen. Typically, T cell activation requires recognition of cognate antigen presented by MHC, however, BiTEs act to circumvent this requirement by nonspecifically activating T cells via clustering surface CD3. The close proximity of the target tumor cells facilitated by Fv binding to tumor antigen enables directed tumor cell killing.
The overall objective of this project is to generate novel CXCR7-targeted mAb-based immunotherapeutic proteins and test their ability to reverse cancer progression.
This project will create and test novel therapeutic agents to selectively target and destroy leukemia, GBM, and breast cancer cells, and, importantly, tumor-associated blood vessels. We believe it holds great promise to improve the health and welfare of cancer patients in the US.