Ira Pastan, M.D.
- Center for Cancer Research
- National Cancer Institute
- Building 37, Room 5106
- Bethesda, MD 20892
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, I 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. One of these Lumoxiti has been approved by the FDA for the treatment of leukemia.
- 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.
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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. To accomplish this, we have employed genetic engineering to modify a potent bacterial toxin, so that it will kill cancer cells.
- Pseudomonas exotoxin A (PE) is a three-domain protein. We have produced anti-cancer agents by deleting the binding domain and other non-essential regions of PE and replacing them with the Fv or Fab portion of an antibody that directs the toxin to a target on the cancer cells. These agents are termed "recombinant immunotoxins" (RITs). They kill cells by arresting protein synthesis and inducing apoptosis, a mechanism not employed by other anti-cancer agents. Therefore, they can kill drug resistant cells.
Several different recombinant immunotoxins have been developed in our laboratory and we are now conducting clinical trials with 2 of them. Moxetumomab pasudotox (Lumoxiti) targets CD22 on B cell malignancies and has been approved by the FDA to treat drug resistant Hairy Cell Leukemia. LMB-100 targets mesothelin present on mesothelioma and many other epithelial cancers (pancreas, ovary, lung, bile duct and triple negative breast cancer). We are carrying out clinical trials in mesothelioma and pancreatic cancer.
Contextualizing the Use of Moxetumomab Pasudotox in the Treatment of Relapsed or Refractory Hairy Cell Leukemia.
Enhanced efficacy of mesothelin-targeted immunotoxin LMB-100 and anti-PD-1 antibody in mesothelioma patients and mouse tumor models.
Combining local immunotoxins targeting mesothelin with CTLA-4 blockade synergistically eradicates murine cancer by promoting anti-cancer immunity
Ira Pastan, M.D.
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
AACR Team Science Award, 2014
Humbert Humphrey Award, DHHS, 2019
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Oncotarget 24 May 2016 issue cover
Structural models of Recombinant Immunotoxins.
A. SS1P consists of the disulfide-stabilized heavy chain Fv (VH) (magenta) and light chain Fv (VL) (Cyan) of the antibody SS1P. The VH is linked to a 38-kDa fragment of PE38 that is divided into domain II (gray), domain III (yellow), and part of domain Ib from native PE38. B. SS1-LO10R. 24-kDa fragment of PE24 with six point mutations in domain III designed to eliminate binding to B-cell receptor. Point mutations are marked with red balls. C. LMB-T20. PE24 with six point mutations in domain III designed to diminish T-cell epitopes. D. LMB-T14. PE24 with 10 point mutations in domain III designed to diminish B and T cell epitopes. All models are hypothetical arrangements based on the structures of native PE and immunoglobulin G; they do not represent actual structure determinations.
Ronit Mazor1, Masanori Onda1, Dong Park1,3, Selamawit Addissie1, Laiman Xiang1,*, Jingli Zhang2, Raffit Hassan2 and Ira Pastan1
1 Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
2 Thoracic and GI Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
3 New Business Development Department, Medytox Inc., Bundang-gu, Seongnam-si, Gyeonggi-do, South Korea
Oncotarget, Vol. 7, No. 21