William Hawkins, M.D., FACS Research Laboratory

William Hawkins, M.D., FACS is a surgical oncologist and researcher focusing on improving outcomes for pancreatic cancer patients. Before joining the Hollings Cancer Center, he was a member of the Senior Leadership for the Alvin J. Siteman Cancer Center, where he co-chaired their cancer center’s research investment program. As the newly appointed Deputy Director at Hollings, Dr. Hawkins aims to promulgate collaborative team science and multi-disciplinary exchanges on a larger scale with the goal of improving detection, treatment, and survival from cancer here in South Carolina.

As a clinician who cares for patients with pancreatic cancer, the dire need for a novel therapeutic approach is painfully evident. Dr. Hawkins will continue his research on novel therapies for the treatment of pancreatic cancer. He will also continue to serve as a Co-Director of the Washington University of Saint Louis Specialized Programs of Research Excellence (SPORE) Team in Pancreatic Cancer. He is expanding the team of clinicians and researchers to address this urgent need by through collaborations with MUSC faculty. Their work is crucial in improving the outcomes for patients with pancreatic cancer through discovery, resource building, and innovation. The Washington University Pancreatic Cancer SPORE, is one of only three pancreatic cancer SPORES in the nation. Continuing this research program helps put MUSC at the forefront of this battle. It is a step towards a more hopeful future in the fight against this disease.

His personal research focuses on systematically developing and testing novel strategies for treating pancreatic adenocarcinoma. Learn more about Dr. Hawkins's personal research.

Dr. Hawkins will continue to see patients with solid malignancies. For his clinical profile please see his clinical webpage.

Since 2008, Dirk Spitzer, Ph.D., has worked in the William Hawkins Lab at Washington University in Saint Louis. His research led to the development of targeted TR3 therapeutics for cancer biomarkers mesothelin and MUC16. These biomarkers are well-characterized and are highly present on the surface of several human cancers, including pancreatic and ovarian cancers. This technology provides much-needed anticancer therapeutics for these cancers.

Now, at MUSC and continuing his work with Hawkins, Spitzer can align his research with the Hollings Cancer Center, where he says he will have more opportunities to develop his research on the various drug platform technologies closer to clinical application.

 

About Dirk Spitzer, Ph.D.

After finishing a postdoctoral degree at Washington University in Saint Louis, MO, Dirk Spitzer, Ph.D., remained at Washington University, where he developed complement therapeutics, including research in a preclinical mouse model of complement regulatory protein deficiency (Paroxysmal nocturnal hemoglobinuria – PNH, a rare but deadly disease of the blood).

In 2008, he joined William Hawkins, M.D., a clinician/scientist focusing on improving outcomes for pancreatic cancer patients. The researchers in the William Hawkins Lab were investigating new drug concepts for pancreatic cancer therapy with a focus on small molecules initially designed for tumor imaging. When Dr. Spitzer joined the lab, he was tasked to explore a novel research path involving the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) biologic. This potential anticancer drug induces cell death in a variety of cancer cells by interacting with death receptors. TRAIL, however, must form a homotrimer to become biologically active. Attempts to produce bioactive TRAIL from monomers have failed for various reasons, limiting its therapeutic potential.

As such, Dr. Spitzer transitioned from his complement therapeutics research to pursue optimizing TRAIL research to overcome its limitations. He subsequently developed a novel concept to produce human TRAIL from mammalian cells as a fusion protein (TR3). TR3 is comprised of three consecutive extracellular TRAIL domains fused together in a head-to-tail configuration, encoded by a single DNA construct. This design provides improved stability without impacting the killing ability of TRAIL and is considered a unique platform technology with the ability of adding genetically encoded cancer cell targeting moieties to the trimer in a well-defined stoichiometric configuration.

More specifically, Dr. Spitzer’s research at Washington University in St. Louis lead to the development of targeted TR3 therapeutics to cancer biomarkers mesothelin and MUC16. Mesothelin is a GPI-linked cell surface protein expressed in mesothelial cells involved in tumor adhesion and metastasis. MUC16 (also known as CA125) is a membrane-anchored mucin that binds with high affinity to mesothelin. These biomarkers are well-characterized and, in comparison to normal host cells and tissues, are highly present on the surface of several human cancers, including pancreatic and ovarian cancers. These cancers lack effective therapies and are among those with the worst survival rates. Thus, there is a great need for new therapeutics.

To help meet this need, Dr. Spitzer modified his TR3 drugs in ways that rendered them highly specific to both mesothelin (using antibody fragments as delivery moieties) and MUC16 (using a mesothelin peptide), with the idea of creating biomarker-selective TR3 drugs (fewer off-targeted side effects) but also to improve drug efficacies (stronger death signaling capacity). This technology provides much-needed anticancer therapeutics for these cancers.

While the researchers in the Hawkins Lab had also developed sigma-2 ligands, initially as imaging agents to identify cancer cells for diagnostic purposes, it was discovered that these ligands were internalizing into the cancer cells, creating a “eureka” moment – offering the possibility of delivering molecules other than fluorescent markers into the cancer cells for therapeutic purposes. This discovery opened the door for exploring complimentary mechanisms, i.e. to augment the TR3-based cell death pathway by creating small-molecule drugs (peptidomimetics and other small-molecule drug cargoes) conjugated to sigma-2 ligands as vehicles.

This seminal work led, amongst others, to a currently funded NIH R01 grant to study an innovative experimental cancer therapeutic by chemically linking IAPinh (LCL161) to S2 ligand SW43, resulting in S2/IAPinh for tumor-selective drug delivery and therapy. The researchers hypothesized that S2/IAPinh can be combined with systemic, low-dose chemotherapy to result in synergistic treatment regimens that lead to tumor eradication while systemic toxicities are reduced to a minimum. The study aims to research the following:

Increase the potency of S2/IAPinh via advanced drug formulation.Validate drug optimization efforts to identify the ultimate drug formulation, dose, administration route and frequency.Identify synergistic combination drugs for S2/IAPinh-based cancer therapy with an aim to improve  S2/IAPinh-mediated cancer therapy via simultaneous cholesterol blockade, and study the novel drug candidate, S2/IAPinh, in which the S2 ligand SW43 was chemically linked to LCL161, in order to address therapy resistance in pancreatic and ovarian cancer.

Now, at MUSC and continuing his work with Hawkins, the newly-appointed Deputy Director of Hollings Cancer Center, Spitzer can align his research with the Hollings Cancer Center, where he says he will have more opportunities to develop his research on the various drug platform technologies closer to clinical application. His research aims to explore both drugs alone and in combination and eventually perform clinical evaluation in patients diagnosed with pancreatic and ovarian cancers.

His future goals center around developing both existing and new drug platforms – mesothelin- and MUC16-targeted TR3 biologics as well as sigma2-ligand based drug conjugates (S2/IAPinh and S2/Erastin [ACXT-3102]) toward the clinical arena, alone and in combination with each other and clinically approved pathway enhancers.

Spitzer has received funding from the Department of Defense, NIH Grants, including an R01, R21, and as a key investigator in NCI SPORE grants for pancreatic cancer.

You can read more about his exciting research in his most recent papers:

The novel drug candidate S2/IAPinh improves survival in models of pancreatic and ovarian cancer. Sci Rep 14, 6373 (2024). DOI: 10.1038/s41598-024-56928-z 

Cytotoxic sigma-2 ligands trigger cancer cell death via cholesterol-induced-ER-stress. Cell Death Dis 15(5), 309 (2024). DOI: 10.1038/s41419-024-06693-8