Ira Pastan, M.D.
Dr. Pastan’s contributions to medical research include
- The discovery with R. Perlman of a new gene regulatory mechanism whereby many quiescent genes are activated by cyclic AMP and its DNA-binding partner CRP.
- Receptor studies which provided the first evidence that peptide hormones bind to receptors on the surface cells, and the use of fluorescence methods to visualize the binding and internalization of insulin and other ligands by living cells, to measure their diffusion rates on the membrane before clustering and internalization, and to demonstrate that different ligands, including viruses, enter cells together in the same vesicles.
- Research on the EGF receptor, which showed that the EGF-R (onco)gene is amplified and over-expressed in many human cancers, the cloning and sequencing of the EGF-R cDNA and with Doug Lowy, the demonstration that over-expression of EGF-R in the presence of EGF can transform normal cells into cancer cells. These studies provided essential evidence that antibodies able to inactivate the EGF receptor could be useful in treating many cancers.
- Studies with M. Gottesman on the biochemical basis of multi-drug resistance in cancer therapy, which involved the isolation of the first human multi-drug resistance gene (MDR1) gene and the demonstration that MDR1 encodes a multi-drug transporter that is highly expressed in many human cancers.
- The development of recombinant immunotoxins for the treatment of cancer.. Working with R. Kreitman and D. FitzGerald he used protein engineering to produce novel chimeric proteins composed of an Fv that targets a protein on the surface of a cancer cell and a portion of a powerful protein toxin.
- The discovery of mesothelin (with M.C. Willingham) and the demonstration that it is an excellent target for antibody based cancer therapies, because of its high expression on many cancers and lack of expression on essential normal organs.
Immunotoxin Therapy of Cancer
1.2 million Americans develop cancer each year and about 500,000 die from the disease. To improve the therapy of cancer new approaches and drugs with new mechanisms of action are needed. We are developing a treatment that incorporates both these principles. We employ genetic engineering to modify a potent bacterial toxin, which is designed to kill many different types of cells, to an agent that kills cancer cells.
Pseudomonas exotoxin A (PE) is a three-domain protein composed of 613 amino acids. We have produced anti-cancer agents by deleting the binding domain of PE (aa 1-252), and replacing it with the Fv portion of an antibody that directs the toxin to a target on cancer cells. These agents are termed "recombinant immunotoxins" (RITs). They kill cells by arresting protein synthesis, a mechanism not employed by other anti-cancer agents.
Several different recombinant immunotoxins have been developed in our laboratory and we are now conducting clinical trials with 2 of them. Moxetumomab pasudotox (HA22) targets CD22 on B cell malignancies and LMB-100 targets mesothelin present on mesothelioma and many other epithelial cancers (pancreas, ovary, lung, bile duct and triple negative breast cancer).
Moxetumomab pasudotox has produced complete remissions in many patients with drug-resistant Hairy Cell Leukemia (HCL) and has also shown anti-tumor activity in childhood acute lymphoblastic leukemia (ALL). Moxetumomab pasudotox is licensed to AsraZeneca, which has just completed a phase 3 trial in drug-resistant Hairy Cell Leukemia.
SS1P is an anti-mesothelin immunotoxin that was evaluated in patients with advanced drug-resistant mesothelioma. When given alone SS1P had limited anti-cancer activity because of its high immunogenicity in patients with normal immune systems, but when combined with cytoxan and pentostatin to suppress the formation of anti-drug antibodies (ADAs) to the bacterial toxin, several striking and long-term remissions were observed. To allow us to give more treatment cycles and achieve better anti-tumor activity without using immuno-suppressive drugs to prevent ADA formation, we have designed and produced a new RIT, LMB-100 (RG7787), in which the major B cell epitopes and T cell epitopes in the toxin have been identified and silenced. LMB-100 is now being evaluated in patients with mesothelioma and pancreatic cancer.
Current laboratory efforts are focused on:
- Investigating the use of rapamycin containing nano-particles to prevent ADAs to LMB-100 and to induce specific immune tolerance to LMB-100 so many treatment cycles can be given,
- Using protein engineering to extend the half-life of immunotoxins in the blood and to decrease their non-specific side effect so higher doses can be given,
- Determining how to effectively combine immunotoxins with other anti-cancer agents (Abraxane, actinomycin D) and check point inhibitors to increase their efficacy, and
- Identifying new targets for immunotoxin-based therapies.
Selected Key Publications
- JOURNAL OF CLINICAL ONCOLOGY. 34: 4171, 2016. [ Journal Article ]
Actinomycin D enhances killing of cancer cells by immunotoxin RG7787 through activation of the extrinsic pathway of apoptosis.PNAS. 113: 10666-10671, 2016. [ Journal Article ]
Dual B- and T-cell de-immunization of recombinant immunotoxin targeting mesothelin with high cytotoxic activity.Oncotarget. 7: 29916, 2016. [ Journal Article ]
In Vitro and In Vivo Activity of the Low-Immunogenic Antimesothelin Immunotoxin RG7787 in Pancreatic Cancer.Molecular Cancer Therapeutics. 13: 2040, 2014. [ Journal Article ]
Phase I Trial of Anti-CD22 Recombinant Immunotoxin Moxetumomab Pasudotox (CAT-8015 or HA22) in Patients With Hairy Cell Leukemia.JOURNAL OF CLINICAL ONCOLOGY. 30: 1822, 2012. [ Journal Article ]
Dr. Ira Pastan was educated at the Boston Public Latin School, Tufts College, and Tufts Medical School. He did his residency at the Yale School of Medicine (1957-1959) and came to NIH in 1959. In 1970, he founded the Laboratory of Molecular Biology in the NCI.
Van Meter Prize, 1971
G. Burroughs Mider Lectureship, National Institutes of Health, 1973
Membership, National Academy of Sciences, 1982
American Academy of Arts and Sciences, 1997
Fellow, American Academy of Microbiology, 1997
Fellow, American Association for the Advancement of Science, 1997
International Feltrinelli Prize for Medicine, 2009
Nathan Davis Award of the AMA for Government Service, 2010
Membership, Institute of Medicine of the National Academies, 2010
|Tapan K. Bera, Ph.D||Associate Scientist|
|Masanori Onda, M.D., Ph.D.||Staff Scientist|
|Chin-Hsien (Emily) Tai||Staff Scientist|
|Dawn Walker M.S.||Technical Laboratory Manager|
|Steven K. Cummings B.S.||Postbaccalaureate Fellow|
|Xiu-Fen Liu Ph.D.||Biologist|
|Zoe Shancer B.S.||Postbaccalaureate Fellow|
|Matthew Williams||Postbaccalaureate Fellow|
|Qi Zhou||Biologist (Contr)|
|Adam Cerise M.D.||Clinical Fellow|
|Junxia Wei Ph.D.||Research Fellow|
|Ronit Mazor Ph.D.||Postdoctoral Fellow (CRTA)|
|Jasmin Leshem Ph.D.||Postdoctoral Fellow (Visiting)|
|Austin Igelman||Postbaccalaureate Fellow|
|Emily King||Postbaccalaureate Fellow|
|Fred Lee||Postbaccalaureate Fellow|
|James O'Brien||Postbaccalaureate Fellow|
Dr. Ira Pastan's group photo