Pancreatic cancer is a devastating disease that kills more than 45,000 Americans each year. About 10% of patients survive five years or more after diagnosis because the disease metastasizes very early in its development and is difficult to treat. More effective and tolerable systemic therapies are needed for treatment of pancreatic cancer patients.
Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreas cancer. Most PDAC expresses the surface antigen mesothelin. Recombinant immunotoxin LMB-100 (previously called RG7787) is a mesothelin-targeted precision therapy that we have tested in the clinic for patients with PDAC. The immunotoxin binds to mesothelin on the cancer cell surface, leading to cancer cell internalization of the bacterial toxin payload and tumor cell death. In the laboratory we are working to identify effective combination therapies that can: 1) enhance delivery of large molecule therapeutics such as LMB-100 to PDAC, and 2) capitalize on immune priming that results from killing tumor cells using a bacterial toxin payload.
Rarer exocrine tumors of the pancreas are typically treated with standard therapies optimized for PDAC. We are interested in learning more about these tumors so that better treatments can be identified, and are actively recruiting patients with these tumor types: 1) Adenosquamous carcinoma of the pancreas (ASCP) is a highly aggressive variant of PDAC that is driven by the Myc oncogene. Minnelide is an oral drug that reduces Myc expression and inhibits growth of ASCP in pre-clinical models. We are currently testing the anti-tumor activity of Minnelide in a Phase II trial specific for patients with ASCP. 2) Pancreatic Acinar Cell Carcinoma (PACC) is an ultra-rare tumor of the pancreas with distinct genetic and pathologic features from PDAC. We are interested in developing pre-clinical models of PACC that will permit detailed study of the tumor’s molecular landscape. Patients with PACC and ASCP are encouraged to participate in the Rare Solid Tumor Natural History study to help us better understand the clinical course of PACC. Travel to Bethesda is not required to participate in the Natural History study.
Dr. Alewine received her M.D. and Ph.D. from the University of Maryland School of Medicine. She completed internal medicine residency in the Osler Medical Training Program at Johns Hopkins Hospital followed by clinical fellowship in Medical Oncology at the National Cancer Institute. She joined the Laboratory of Molecular Biology as an Assistant Clinical Investigator through the support of the Clinical Investigator Development program in 2014 and became a tenure-track investigator through the NIH Lasker Scholar program in 2016.
- Hagerty BL, Pegna GJ, Xu J, Tai CH, Alewine C. Mesothelin-Targeted Recombinant Immunotoxins for Solid Tumors. Biomolecules. 2020;10(7).
- Alewine C, Ahmad M, Peer CJ, Hu ZI, Lee MJ, Yuno A, Kindrick JD, Thomas A, Steinberg SM, Trepel JB, Figg WD, Hassan R, Pastan I. Phase I/II Study of the Mesothelin-targeted Immunotoxin LMB-100 with Nab-Paclitaxel for Patients with Advanced Pancreatic Adenocarcinoma. Clin Cancer Res. 2020;26(4):828-836.
- Avula LR, Rudloff M, El-Behaedi S, Arons D, Albalawy R, Chen X, Zhang X, Alewine C. Mesothelin Enhances Tumor Vascularity in Newly Forming Pancreatic Peritoneal Metastases. Mol Cancer Res. 2020;18(2):229-239.
- El-Behaedi S, Landsman R, Rudloff M, Kolyvas E, Albalawy R, Zhang X, Bera T, Collins K, Kozlov S, Alewine C. Protein Synthesis Inhibition Activity of Mesothelin Targeting Immunotoxin LMB-100 Decreases Concentrations of Oncogenic Signaling Molecules and Secreted Growth Factors. Toxins (Basel). 2018;10(11).
- Kolyvas E, Rudloff M, Poruchynsky M, Landsman R, Hollevoet K, Venzon D, Alewine C. Mesothelin-targeted immunotoxin RG7787 has synergistic anti-tumor activity when combined with taxanes. Oncotarget. 2017;8(6):9189-9199.
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Molecular Biology and Biochemistry
This page was last updated on Monday, April 11, 2022