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Rogers Laboratory Research | Overview


The Rogers laboratory works to develop new therapies for endometriosis, cancer, and blinding eye disease. To achieve these goals we use mouse models of disease, mouse genetic approaches, high-throughput screening, CRISPR genome editing, as well as standard cell culture and molecular biology techniques.

Historically, the Rogers lab has focused on the regulation of neovascularization in the tumor microenvironment. Recently this has expanded to include the role of VEGF in the etiology of endometriosis and associated pain. We have successfully generated a mouse model of endometriosis associated pain that is suitable for validation using existing therapeutics. This model exhibits lesion architecture that is highly similar to that of human lesions. We are currently using this model to identify drugs that can be repurposed to treat endometriosis, as well as to validate new therapeutic targets.

Other ongoing work relies on the observation that tumor vessels are necessary, not only to support tumor metabolism, providing oxygen and nutrients and carry away waste, but the microvasculature and cytokines that regulate angiogenesis (e.g., VEGF, IL-6, IL-8) are key determinants of the antitumor immune response. For example, VEGF inhibits T-cell and dendritic cell activation and stimulates endothelial cell expression of Fas-ligand, inducing T-cell apoptosis and inhibiting infiltration. As a result, my colleague Steve Hodi recently showed in a Phase I trial that the activity of the immunooncology drug ipilimumab (a checkpoint inhibitor) is dramatically potentiated by anti-VEGF therapy (bevacizumab). In addition, angiocrine signaling is a key mediator of tumor cell survival and proliferation and the perivascular niche is the preferred location for tumor stem cells. I use genetics to identify new regulators of angiogenesis. I then work to identify drug-like molecules that can affect protein function, thereby identifying new leads for drugs that can be used to treat a wide variety of conditions, including cancer, blinding eye disease, and endometriosis.

Capillary morphogenesis gene 2 (CMG2)/high-throughput screening

An outgrowth of this genetic work is the discovery that the anthrax toxin receptor capillary morphogenesis gene 2 (CMG2) can serve as a target for small-molecule angiogenesis inhibitors. In collaboration with Dr. Kenneth Christensen we demonstrated that the Protective Antigen subunit of anthrax toxin is a potent anti-angiogenic agent. We are currently working with Dr. Christensen, to identify extracellular matrix ligands for CMG2 and are currently mapping peptides from these ligands that bind to CMG2 extracellular domain with the dual goals of understanding CMG2 function and identifying inhibitory peptide ligands for the protein. To identify CMG2 inhibitors we have also developed high-throughput assays for small molecule inhibitors of CMG2 and its closest relative tumor endothelial marker 8 (TEM8). Screening of natural product libraries in collaboration with Dr. Jon Clardy has led to the identification of two different classes of inhibitors for CMG2. One, penta-galloyl glucose (PGG) had known antiangiogenic activity, but no receptor with appropriate affinity, while the other is structurally novel. Ongoing work has also identified hits from synthetic small molecule libraries for both CMG2, including one that potentiates angiogenesis, suggesting that it stabilizes CMG2 in an active conformation. These small molecules are likely to serve as good leads for both anthrax-protective agents as well as anti-angiogenic agents.

Our expertise with high throughput screening has been further leveraged in a collaboration with Dr. Bruce Zetter to develop assays to identify small molecule antagonists of antizyme inhibior.