|LETTER TO THE EDITOR
|Year : 2017 | Volume
| Issue : 4 | Page : 697-698
Surendra Nath Sehgal: A pioneer in rapamycin discovery
Division of Child Neurology, Department of Pediatrics, University of Arkansas for Medical Sciences, Little rock, Arkansas, USA
|Date of Web Publication||30-Jul-2018|
Dr. Debopam Samanta
Division of Child Neurology, Department of Pediatrics, University of Arkansas for Medical Sciences, Little rock, Arkansas
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Samanta D. Surendra Nath Sehgal: A pioneer in rapamycin discovery. Indian J Cancer 2017;54:697-8
The mammalian/mechanistic target of rapamycin (mTOR) signaling pathway integrates both intracellular and extracellular signals and serves as a central regulator of cell metabolism, growth, proliferation, and survival. Deregulations of multiple elements of the mTOR pathway such as PI3K amplification/mutation, PTEN loss of function, AKT overexpression, and S6K1, 4EBP1, and eIF4E overexpression have been related to many types of cancers. Everolimus (derivative of sirolimus) and sirolimus are inhibitors of mTOR. Safety and efficacy of everolimus in the treatment of subependymal giant cell astrocytoma and angiomyolipoma associated with tuberous sclerosis have been proved in several randomized controlled trials., Recently, studies have shown its effectiveness in seizure control in refractory epilepsy patients with tuberous sclerosis. The mTOR inhibitors have been approved for use in advanced kidney cancers, prevention of organ rejection after renal transplant, progressive or metastatic pancreatic neuroendocrine tumors, HER2-negative, hormone receptor-positive breast cancer in postmenopausal women, prevention of organ rejection after liver transplantation, and progressive, well-differentiated nonfunctional, neuroendocrine tumors of gastrointestinal or lung origin with unrespectable, locally advanced, or metastatic disease. In addition, sirolimus has Food and Drug Administration (FDA)-approved indication to treat lymphangioleiomyomatosis – a rare and progressive lung disease. Unfortunately, the scientist, Dr. Surendra (Suren) Nath Sehgal, who discovered rapamycin (another name for sirolimus), had not been remembered with much fanfare recently.
Mr. Ajai Sehgal, Dr. Suren Sehgal's son, provided some little-known facts about his early life and career. Dr. Sehgal was born in the small village of Khushab, India in 1932. He was motivated by his father who had a pharmaceutical factory to study pharmaceutical science. He received a B. Pharm and an M. Pharm from the Banaras Hindu University in 1952 and 1953, respectively. Dr. Sehgal completed his Ph.D. from Bristol University in England in 1957 and accepted a post-doc fellowship at National Research Council of Canada. In 1959, he joined Ayerst Research Lab in Montreal, Canada. Dr. Sehgal recruited several friends to this research lab to form a core group that was instrumental to the landmark discovery discussed below.
In 1972, a streptomycete was isolated by Sehgal et al. from an Easter Island soil sample, collected by a Canadian scientific expedition team in 1964, and was found to have antifungal properties with inhibition of Candida albicans, Microsporum gypseum, and Trichophyton granulosum. Dr. Sehgal pioneered in the characterization and identification of this antibiotic-producing microorganism called Streptomyces hygroscopicus. As Easter Island (a Chilean island in the southeastern Pacific Ocean) is known as Rapa Nui by the locals, this compound was named as rapamycin. Subsequent characterization, however, showed that rapamycin has immunosuppressive properties, and it inhibits antigen-induced T-cell and B-cell proliferation. This additional information prevented its potential development as an antifungal drug due to a concern of the immunosuppressive side effects. Further research would have been stopped without the determined effort by Dr. Sehgal, as he believed that rapamycin possessed novel properties beyond its immunosuppressive activities. He sent a sample of rapamycin to the National Cancer Institute (NCI) for antitumor activity screening. Rapamycin was found to inhibit the growth of a number of tumor cell lines, including mammary, colon 26, B16 43 melanocarcinomas, and EM ependymoblastoma. Based on these test results, NCI advanced rapamycin as a priority drug.
Unfortunately, the concept of signal transduction blockage was completely unknown at that time, and the research related to rapamycin was aborted in 1982 with the closing down of the Ayerst Montreal Laboratories. But Dr. Sehgal continued his effort to revive rapamycin research for 6 years. In 1987, American Home Products merged its two drug subsidiaries, Wyeth and Ayerst, and in May 1988, Sehgal sent a memo about rapamycin that allowed for the animal testing of rapamycin, which proved its excellent immunosuppressant effect. The drug as an immunosuppressant was resurrected, and Dr. Sehgal successfully convinced the NCI to resume the research of its anticancer properties. After several successful clinical studies, in 1999 FDA's Advisory Committee made a unanimous recommendation for an approval of Rapamune. The story of rapamycin discovery illustrates the process of the basic research and its translation to clinical use in coordination with a scientist's unwavering effort in scientific advancement. Dr. Barry Kahan aptly said that the name of the drug Dr. Sehgal discovered should be designated “s u rolimus” rather than s i rolimus as a fitting homage to a gentleman who had given so much to this enterprise.
After the discovery of its antitumor activity, it was found that rapamycin binds to a target protein or target of rapamycin (TOR), which is highly conserved evolutionarily. It was also found that the TOR pathway has a central role in the regulation of cell growth (cell size or mass) and proliferation (cell number), and cell response to stress, by acting at the catalytic subunit of two protein kinase complexes: mTOR complexes 1 and 2 (mTORC1/2). mTORC1 signaling is switched on by several oncogenic signaling pathways such as Ras/Raf/MEK/ERK pathway and the phosphoinositide 3-kinase (PI3K)/AKT (PKB) pathway and is accordingly hyperactive in the majority of cancers. Rapamycin does not directly inhibit the catalytic (kinase) activity of mTOR; instead, it binds, together with a small protein, an immunophilin termed FKBP12, specifically to mTORC1, but not mTORC2, to a domain adjacent to the kinase active site. As rapamycin inhibits only some of the functions of mTORC1, further research effort was directed to the discovery of other rapamycin analogs such as everolimus. Inhibiting the downstream of mTOR, especially mTORC1, may potentially play a critical role in cancer therapy in future as inhibition of mTORCs triggers a number of feedback loops toward upstream signaling pathways with subsequent activation to promote cancer cell survival and metastasis. Moreover, Gaur et al. noted that the mTOR inhibitor can have a role in restoring chemosensitivity to adriamycin/cisplatin. Furthermore, Teachey et al. reported that the mTOR activates the degradation of cyclin-dependent kinases such as CDK1 which increases synthesis of dihydrofolate reductases. By decreasing this enzyme, mTOR inhibitors such as sirolimus and temsirolimus promote tumor sensitivity to agents such as methotrexate in preclinical models of acute lymphoblastic leukemia.
Dr. Sehgal received a Lifetime Achievement Award by the Indian Society of Organ Transplantation in 1997. He was diagnosed with metastatic colon cancer in 1998. His physician treated him with Rapamune for liver metastasis, and he was pleased that it had extended his life. Ultimately, he passed away in 2003 after 40 years of active research in rapamycin.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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