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Ira Pastan, M.D.

Ira Pastan, M.D.

  • Center for Cancer Research
  • National Cancer Institute

RESEARCH SUMMARY

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.

Areas of Expertise

Protein and Antibody Engineering
Immunotoxins
Mesothelin
Immunogenicity

Information for Patients

Learn more about our clinical trials and the highly specialized care teams that lead them. 

Research

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.
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Molecular Biology Section 2019

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.

NIH Scientific Focus Areas
Biomedical Engineering and Biophysics
Cancer Biology
Clinical Research
Immunology
Molecular Biology and Biochemistry

Publications

Selected Key Publications

Multiple proteases are involved in mesothelin shedding by cancer cells.

Liu X, Chan A, Tai CH, Andresson T, Pastan I.
Commun Biol.. 3(1): 728, 2020. [ Journal Article ]

Contextualizing the Use of Moxetumomab Pasudotox in the Treatment of Relapsed or Refractory Hairy Cell Leukemia.

Kreitman RJ, Pastan I.
Oncologist. 25(1): e170-e177, 2020. [ Journal Article ]

Enhanced efficacy of mesothelin-targeted immunotoxin LMB-100 and anti-PD-1 antibody in mesothelioma patients and mouse tumor models.

Jiang Q, Ghafoor A, Mian I, Rathkey D, Thomas A, Alewine C, Sengupta M, Ahlman MA, Zhang J, Morrow B, Steinberg SM, Pastan I, and Hassan R
Sci Transl Med. . 12(550): eaaz7252, 2020. [ Journal Article ]

Mesothelin Immunotherapy for Cancer: Ready for Prime Time?

Hassan R., Thomas, A., Alewine, C., Le, D.T., Jaffee, E.M., and Pastan, I.
JOURNAL OF CLINICAL ONCOLOGY. 34: 4171, 2016. [ Journal Article ]

Combining local immunotoxins targeting mesothelin with CTLA-4 blockade synergistically eradicates murine cancer by promoting anti-cancer immunity

Leshem, Y., O’Brien, J., Liu, X., Bera, T.K., Terabe, M., Berzofsky, J.A., Bossenmaier, B., Niederfellner, G., Tai, C.-H., Reiter, Y., and Pastan, I.
Cancer Immunol. Res. . 5: 685-694, 2017. [ Journal Article ]

Job Vacancies

There are no open positions at this time. Check back again later, or take a look at CCR's Careers page.

Team

Scientist (Contr.)
Dawn Walker, M.S.
Lab Manager
Emily J. Danoff, Ph.D.
Postdoctoral Fellow (Visiting)
Wenlong Liu, Ph.D.
Biologist
Xiu-Fen Liu, Ph.D.
Microbiologist
Richard Beers
Biologist (Contr)
Qi Zhou
Postbaccalaureate Fellow (CRTA)
Anirban Chakraborty, B.S.

News

Sammies finalist develops new drug for rare form of leukemia

WJLA 24/7 News

Government Matters 2020.06.18 episode

Dr. Ira Pastan, Distinguished Investigator at the National Cancer Institute at NIH, discusses a drug he developed for a rare type of leukemia and its potential to treat other cancers.

 

Moxetumomab Approved by FDA for Hairy Cell Leukemia

September 14, 2018, by NCI Staff

Moxetumomab pasudotox (Moxe) binds CD22 receptors on the surface of cancerous B cells, where it is internalized and processed to release its toxic payload.
Moxetumomab pasudotox (Moxe) binds CD22 receptors on the surface of cancerous B cells, where it is internalized and processed to release its toxic payload. Credit: National Cancer Institute
 

The Food and Drug Administration (FDA) has approved moxetumomab pasudotox (Lumoxiti), a bacterial toxin–based drug, for the treatment of some patients with hairy cell leukemia (HCL). The approval covers the use of moxetumomab in patients with HCL who have already undergone at least two lines of standard treatments. 

The action by FDA makes moxetumomab the first treatment approved for this group of patients. The approval was based on the findings from an 80-patient clinical trial sponsored by the drug’s manufacturer, MedImmune.

In the trial, approximately 30% of patients had a complete disappearance of their cancer (complete response) that lasted for a long period, and side effects from the therapy were few and mostly minor. Overall, 75% of patients in the trial had either a partial response or complete response.

Moxetumomab was originally discovered by Ira Pastan, M.D., and colleagues in NCI’s Center for Cancer Research (CCR), and later licensed to MedImmune/AstraZeneca for clinical development.

“This is an important example of conceptually innovative research conducted at NCI that has come to practical fruition with a commercial partner,” said CCR Director Tom Misteli, Ph.D. “It’s the kind of work made possible by our ability at NCI to pursue long-term, high-risk research, including on rare forms of cancers such as hairy cell leukemia. Moxetumomab will make a difference in the lives of patients with this incurable disease.”

Many people diagnosed with HCL will achieve remission with current treatments, explained the trial’s lead investigator, Robert Kreitman, M.D., of CCR's Laboratory of Molecular Biology.

“But about 30%–40% of those patients will relapse 5 to 10 years after their first treatment,” Dr. Kreitman continued.

As patients receive further treatments, although they may go into remission again, the length of those remissions gets shorter and shorter, and the toxicities of the treatments accumulate, he explained. For these patients, few effective treatments exist, which is what makes this new approval so important.

“Moxetumomab represents a promising nonchemotherapeutic treatment for HCL, addressing an unmet medical need for patients,” Dr. Kreitman said.

Moxetumomab includes a special boxed warning for clinicians and patients about the risk of capillary leak syndrome, in which fluid and proteins leak out of tiny blood vessels into surrounding tissues.

Further details on moxetumomab and the clinical trial on which FDA's approval was based are available in this June 2018 Cancer Currents post.

Covers

Oncotarget Cover - May 2016

Oncotarget 24 May 2016 issue cover

Published Date

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. 

Citation

Dual B- and T-cell de-immunization of recombinant immunotoxin targeting mesothelin with high cytotoxic activity

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