Ira Pastan (born in Winthrop, Massachusetts June 1, 1931) is an American scientist at the National Cancer Institute. 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, was an American poet.
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.
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.
Additionally, with his colleague Jesse Roth, he 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, but 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 cyclophosphamide 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.
An exotoxin is a toxin secreted by bacteria. An exotoxin can cause damage to the host by destroying cells or disrupting normal cellular metabolism. They are highly potent and can cause major damage to the host. Exotoxins may be secreted, or, similar to endotoxins, may be released during lysis of the cell. Gram negative pathogens may secrete outer membrane vesicles containing lipopolysaccharide endotoxin and some virulence proteins in the bounding membrane along with some other toxins as intra-vesicular contents, thus adding a previously unforeseen dimension to the well-known eukaryote process of membrane vesicle trafficking, which is quite active at the host–pathogen interface.
An immunotoxin is an artificial protein consisting of a targeting portion linked to a toxin. When the protein binds to that cell, it is taken in through endocytosis, and the toxin kills the cell. They are used for the treatment of some kinds of cancer and a few viral infections.
Sorting nexin-1 is a protein that in humans is encoded by the SNX1 gene. The protein encoded by this gene is a sorting nexin. SNX1 is a component of the retromer complex.
Mesothelin, also known as MSLN, is a protein that in humans is encoded by the MSLN gene.
Heparin-binding EGF-like growth factor (HB-EGF) is a member of the EGF family of proteins that in humans is encoded by the HBEGF gene.
Epiregulin (EPR) is a protein that in humans is encoded by the EREG gene.
An anti-CD22 immunotoxin is a monoclonal antibody targeting CD22 linked to a cytotoxic agent. As of August 2009, it was studied in the treatment of some types of B-cell cancer. It binds to CD22, a receptor protein on the surface of normal B cells and B-cell tumors, and, upon internalization, kills the cells, acting as immunotoxin.
Cadherin EGF LAG seven-pass G-type receptor 3 is a protein that in humans is encoded by the CELSR3 gene.
Cadherin EGF LAG seven-pass G-type receptor 2 is a protein that in humans is encoded by the CELSR2 gene.
Neuropeptides B/W receptor 1, also known as NPBW1 and GPR7, is a human protein encoded by the NPBWR1 gene. As implied by its name, it and related gene NPBW2 are transmembranes protein that bind Neuropeptide B (NPB) and Neuropeptide W (NPW), both proteins expressed strongly in parts of the brain that regulate stress and fear including the extended amygdala and stria terminalis. When originally discovered in 1995, these receptors had no known ligands and were called GPR7 and GPR8, but at least three groups in the early 2000s independently identified their endogenous ligands, triggering the name change in 2005.
Cadherin EGF LAG seven-pass G-type receptor 1 also known as flamingo homolog 2 or cadherin family member 9 is a protein that in humans is encoded by the CELSR1 gene.
EGF-containing fibulin-like extracellular matrix protein 1 is a protein that in humans is encoded by the EFEMP1 gene.
Adenylyl cyclase type 5 is an enzyme that in humans is encoded by the ADCY5 gene.
The human gene UBR1 encodes the enzyme ubiquitin-protein ligase E3 component n-recognin 1.
Fc receptor-like protein 5 is a protein that in humans is encoded by the FCRL5 gene. FCRL5 has also been designated as CD307.
TCR gamma alternate reading frame protein, also known as TARP, is a human gene.
A431 cells are a model human cell line used in biomedical research.
John Mendelsohn was a president of the University of Texas MD Anderson Cancer Center in Houston. He was an internationally recognized leader in cancer research.
In molecular biology, the CAS/CSE protein family is a family of proteins which includes mammalian cellular apoptosis susceptibility (CAS) proteins and yeast chromosome-segregation protein, CSE1. CAS is involved in both cellular apoptosis and proliferation. Apoptosis is inhibited in CAS-depleted cells, while the expression of CAS correlates to the degree of cellular proliferation. Like CSE1, it is essential for the mitotic checkpoint in the cell cycle, and has been shown to be associated with the microtubule network and the mitotic spindle, as is the protein MEK, which is thought to regulate the intracellular localization of CAS. In the nucleus, CAS acts as a nuclear transport factor in the importin pathway. The importin pathway mediates the nuclear transport of several proteins that are necessary for mitosis and further progression. CAS is therefore thought to affect the cell cycle through its effect on the nuclear transport of these proteins. Since apoptosis also requires the nuclear import of several proteins, it has been suggested that CAS also enables apoptosis by facilitating the nuclear import of at least a subset of these essential proteins.
Thomas A. Waldmann was an American immunologist who has worked on therapeutic monoclonal antibodies to the IL-2 receptor, Interleukin 15 (IL-15), and Adult T-cell Leukemia (ATL). Until the week he died, he was an active distinguished investigator at the Lymphoid Malignancies Branch of the National Cancer Institute.
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