Ira Pastan

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Dr. Pastan November 2012

Ira Pastan (born Winthrop, Massachusetts June 1, 1931) is an American scientist. He is a member of the National Academy of Sciences, a Fellow of the AAAS and the American Society of Microbiology. In 2009, he was awarded the prestigious International Antonio Feltrinelli Prize for Medicine. His wife, Linda Pastan, is an accomplished American poet.

Biography

Pastan attended the Boston Public Latin School, Tufts College, and Tufts Medical School. He did his residency at the Yale School of Medicine (1957-1959).

Pastan conducted research training in endocrinology at NIH with Earl Stadtman starting in 1959. In 1970, he founded the Laboratory of Molecular Biology (LMB) in the National Cancer Institute (the largest Institute of the National Institutes of Health). He is currently co-chief of the LMB and is working on various Immunotoxin Therapies.

Research Activities

Pastan pioneered the field of receptor biology in animal cells and identified a major receptor mediated pathway of gene regulation in bacteria. With Robert L. Perlman he established the first general mechanism of positive gene regulation in bacteria, showing that cyclic AMP and its receptor protein CRP (cyclic AMP receptor protein) positively regulated the activity of many genes.[1][2] These studies serve as a paradigm for the mechanism of action of cyclic AMP and steroid hormones on gene expression in animal cells. His current research is focused on developing Recombinant Immunotoxins (RITs) as a new treatment for cancer. Gene splicing techniques are used to make chimeric proteins in which the Fv of an antibody, preferentially binding to a cancer cell, is attached to a potent bacterial toxin.

Pastan, with his colleague Jesse Roth, was the first to clearly demonstrate the presence of specific protein receptors on the surface of animal cells.[3][4][5] To explain the biochemical basis of hyperthyroidism, Pastan showed that antibodies from the serum of patients with hyperthyroidism specifically activated thyroid gland adenylate cyclase, providing an immunological mechanism for hyperthyroidism.[6] He then proceeded to study hormone interactions with living cells using fluorescence photo-bleaching to visualize polypeptide hormone-receptor complexes bound to the membrane of living cells. He showed these complexes were highly mobile and clustered before entry into cells, and measured their lateral diffusion coefficients.[7][8] In collaboration with Mark Willingham, he developed and used video intensified microscopy to visualize fluorescently labeled insulin and EGF forming clusters on the surface of living cells prior to entry through the endocytic pathway.[9][10] These studies identified the pathway by which growth factors enter cells and established a mechanism that helped explain down-regulation of receptors and the loss of growth factor responsiveness.


Following the identification of the EGF receptor by Stanley Cohen, Pastan and colleagues made several seminal advances that identified the EGF receptor as a proto-oncogene. Besides being one of the first 3 laboratories to obtain the DNA sequence of the EGF receptor,[11] they showed that the EGF receptor gene was amplified, rearranged and over-expressed in many cancer cells including squamous cell carcinomas,[12][13] and with Doug Lowy showed that over-expression of the EGF receptor in the presence of EGF is sufficient to transform normal 3T3 cells and therefore is a proto-oncogene.[14] Altogether these studies provided much of the framework that ultimately led to the use of antibodies targeted to the EGF receptor as a cancer therapy.

Pastan is currently developing a new therapy for cancer by making fusion proteins composed of the Fv portion of monoclonal antibodies directed at receptor proteins on cancer cells fused to a genetically modified form of a powerful bacterial toxin, Pseudomonas exotoxin A.[15] Three of these genetically engineered proteins, which he named recombinant immunotoxins (RITs), are being tested in humans with various forms of cancer. One of these, HA22 or Moxetumomab pasudotox (Moxe), targets CD22 on B cell malignancies; it has produced many complete and durable remissions in chemotherapy resistant Hairy cell leukemia and is now in a phase 3 trial to gain FDA approval.[16][17] Moxe also produced complete remissions in children with drug resistant Acute Lymphoblastic Leukemia and is being developed for the treatment of that disease.

Another immunotoxin, SS1P,[18] targets the mesothelin antigen. Mesothelin was discovered by Pastan and his colleague Mark Willingham and is a promising target for cancer immunotherapy, because it is expressed on many cancers: mesothelioma, ovarian, lung, pancreatic stomach cancers and cholangiocarcinoma, yet not on essential organs.[19][20][21] SS1P has shown anti-tumor activity in a phase I trial when combined with chemotherapy. In a recently completed clinical trial, SS1P was combined with the immunosuppressive drugs cyclophospamide and pentostatin and produced remarkable major and sustained tumor regressions lasting up to 2 years in patients with advanced chemotherapy resistant mesothelioma.[22] Tumor shrinkage of this magnitude and duration has never before been observed in mesothelioma.

Pastan’s current efforts are directed at improving the activity and usefulness of immunotoxins he has developed. One of the major obstacles to the success of RIT therapy is that antibodies often form and neutralize the RIT preventing additional treatment cycles. Pastan has developed methods to make active RITs in which the major B cell and T cell epitopes have been identified and silenced.[23][24] An RIT with reduced immunogenicity that targets mesothelin expressing cancers is being prepared for clinical trials to begin in 2014.

Awards

References

  1. ↑ Pastan, I. and Perlman, R.L: The role of the lac promoter locus in the regulation of β-galactosidase synthesis by cyclic 3′,5′-AMP. Proc. Natl. Acad. Sci. USA 61: 1336-1342, 1968
  2. ↑ Pastan, I. and Perlman, R.L.: Cyclic adenosine monophosphate in bacteria. (Review-lead article). Science 169: 339-344, 1970
  3. ↑ Pastan, I., Roth, J., and Macchia, V.: Binding of hormone to tissue: The first step in polypeptide hormone action. Proc. Natl. Acad. Sci. USA 56: 1802-1809, 1966
  4. ↑ Lefkowitz, R., Roth, J., Pricer, W., and Pastan, I.: ACTH receptors in the adrenal: Specific binding of ACTH-125I and its relation to adenyl cyclase. Proc. Natl. Acad. Sci. USA 65: 745-752, 1970
  5. ↑ Lefkowitz, R., Roth, J., and Pastan, I.: Effects of calcium on ACTH stimulation of the adrenal: Separation of hormone binding from adenyl cyclase activation. Nature 228: 864-866, 1970
  6. ↑ Levey, G.S. and Pastan, I.: Activation of thyroid adenyl cyclase by long-acting thyroid stimulator. Life Sci. 9: 67-73, 1970
  7. ↑ Schlessinger, J., Shechter, Y., Cuatrecasas, P., Willingham, M., and Pastan, I.: Quantitative determination of the lateral diffusion coefficients of the hormone-receptor complexes of insulin and epidermal growth factor on the plasma membrane of cultured fibroblasts. Proc. Natl. Acad. Sci. USA 75: 5353-5357, 1978
  8. ↑ Schlessinger, J., Shechter, Y., Willingham, M.C., and Pastan, I.: Direct visualization of the binding, aggregation and internalization of insulin and epidermal growth factor on fibroblastic cells. Proc. Natl. Acad. Sci. USA 75: 2659-2663, 1978
  9. ↑ Willingham, M.C. and Pastan, I.: The visualization of fluorescent proteins in living cells by video intensification microscopy (VIM). Cell 13: 501-507, 1978
  10. ↑ Willingham, M.C. and Pastan, I.: The receptosome: An intermediate organelle or receptor-mediated endocytosis in cultured fibroblasts. Cell 21: 67-77, 1980
  11. ↑ Xu, Y-H., Ishii, S., Clark, A.J.L., Sullivan, M., Wilson, R.K., Ma, D.P., Roe, B.A., Merlino, G. T., and Pastan, I.: Human epidermal growth factor receptor cDNA is homologous to a variety of RNAs overproduced in A431 carcinoma cells. Nature 309: 806-810, 1984
  12. ↑ Merlino, G.T., Xu, Y-H., Ishii, S., Clark, A.J.L., Semba, K. Toyoshima, K., Yamamoto, T., and Pastan, I.: Amplification and enhanced expression of the epidermal growth factor receptor gene in A431 human carcinoma cells. Science 224: 417-419, 1984
  13. ↑ Merlino, G.T., Xu, Y.-h., Richert, N., Clark, A.J.L., Ishii, S.,Banks-Schlegel, S., and Pastan, I.: Elevated epidermal growth factor receptor gene copy number and expression in a squamous carcinoma cell line. J. Clin. Invest. 75: 1077-1079, 1985
  14. ↑ Velu, T.J., Beguinot, L., Vass, W.C., Willingham, M.C., Merlino, G.T., Pastan, I., and Lowy, D.R.: EGF-dependent transformation by a human EGF receptor proto-oncogene. Science 238: 1408-1410, 1987
  15. ↑ Hwang, J., FitzGerald, D.J.P., Adhya, S., and Pastan, I.: Functional domains of pseudomonas exotoxin identified by deletion analysis of the gene expressed in E. coli. Cell 48: 129-136, 1987
  16. ↑ Kreitman, R.J., Wilson, W.H., Bergeron, K., Raggio, M., Stetler-Stevenson, M., FitzGerald, D.J., and Pastan, I.: Efficacy of the anti-CD22 recombinant immunotoxin BL22 in chemotherapy-resistant Hairy-cell leukemia. N. Engl. J. Med. 345: 241-247, 2001
  17. ↑ Kreitman, R.J., Tallman, M.S., Robak, T., Coutre, S., Wilson, W.H., Stetler-Stevenson, M., FitzGerald, D.J., Lechleider, R., and Pastan, I.: Phase I trial of anti-CD22 recombinant immunotoxin Moxetumomab pasudotox (CAT-8015 or HA22) in patients with hairy cell leukemia. J. Clin. Oncol. 30: 1822-1828, 2012
  18. ↑ Chowdhury, P.S. and Pastan, I. Improving antibody affinity by mimicking somatic hypermutation in vitro. Nature Biotechnol. 17: 568-572, 1999
  19. ↑ Chang, K., Pai, L.H., Batra, J.K., Pastan, I., and Willingham, M.C.: Characterization of the antigen (CAK1) recognized by monoclonal antibody K1 that is present on ovarian cancers and normal mesothelium. Cancer Res. 52: 181-186, 1992
  20. ↑ Chang, K., Pastan, I., and Willingham, M.C.: Isolation and characterization of a monoclonal antibody, K1, reactive with ovarian cancers and normal mesothelium. Int. J Cancer. 50: 373-381, 1992
  21. ↑ Chang, K. and Pastan, I.: Molecular cloning of mesothelin, a differentiation antigen present on mesothelium, mesotheliomas and ovarian cancers. Proc. Natl. Acad. Sci. USA 93: 136-140, 1996
  22. ↑ Hassan, R., Miller, A.C., Sharon, E., Thomas, A., Reynolds, J.C., Ling, A., Kreitman, R.J., Miettinen, M.M., Steinberg, S.M., Fowler, D.H., and Pastan, I.: Major cancer regressions in mesothelioma after treatment with an anti-mesothelin immunotoxin and immune suppression. Sci. Transl. Med. 5: 208ra147, 2013
  23. ↑ Liu, W., Onda, M., Lee, B., Kreitman, R.J., Hassan, R., Xiang, L., and Pastan, I.: Recombinant immunotoxin engineered for low immunogenicity and antigenicity by identifying and silencing human B-cell epitopes. Proc. Natl. Acad. Sci. USA 109: 11782-11787, 2012
  24. ↑ Mazor, R., Vassall, A.N., Eberle, J.A., Beers, R., Weldon, J.E., Venzon, D.J., Tsang, K.Y., Benhar, I., and Pastan, I.: Identfication and elimination of an immunodominant T-cell epitope in recombinant immunotoxins based on Pseudomonas exotoxin A. Proc. Natl. Acad. Sci. USA 109: E3597-3603, 2012

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