Discovery of Specific Gene Could Lead to New Treatment Options

gene expression; follicular lymphoma: gene expression; follicular lymphomaWhile follicular lymphoma is associated with several alterations of the cell's DNA, it has been unclear which gene or genes are involved in its development. However, the recent discovery of a specific gene, which is frequently missing or malfunctioning in follicular lymphoma, could lead to new treatment strategies for this patient population (Sci Transl Med 2017; doi: 10.1126/scitranslmed.aak9969). Re-activation of the gene, Sestrin1, by reducing the activity of mammalian target of rapamycin complex 1 (mTORC1) hampers tumor growth, according to findings from the lab of Elisa Oricchio, PhD, Professor at the Swiss Institute for Experimental Cancer Research at EPFL in Lausanne, with colleagues from the U.S. and Canada.Elisa Oricchio, PhD: Elisa Oricchio, PhDThis work was carried out in collaboration with the Memorial Sloan Kettering Cancer Center, Cornell University, the University of Lausanne, Goodwin Research Laboratories, Trinity College Dublin, the BC Cancer Agency, the University of British Columbia, and the Princess Margaret Cancer Centre, Toronto. Sestrin1 helps the cell defending itself against DNA damage, for example after exposure to radiation, and oxidative stress. In fact, Sestrin1 is part of the cell's anti-tumor mechanism that stops potentially cancerous cells from growing, explained Oricchio, noting the discovery opens new treatment options. The gene has been described before in different cellular context, “but we demonstrated its importance in follicular lymphoma and potential therapeutic implications,” Oricchio noted. “Most of the target therapies in cancer are designed to block the activity of oncogenes. It's particularly challenging to re-establish the function of tumor suppressor genes or a tumor suppressor gene.” Genetic Abnormalities Follicular lymphoma impacts more than 200,000 people worldwide every year. A form of non-Hodgkin lymphoma, follicular lymphoma develops when the body starts making abnormal B cells. One of the common features of follicular lymphoma is a genetic abnormality between two chromosomes (14 and 18). When chromosomal translocation occurs, the two chromosomes “swap” certain parts with each other. This triggers the activation of a gene that protects cells from dying, making cells virtually immortal—the hallmark of a tumor. Moreover, approximately 30 percent of follicular lymphoma patients also lose a portion of chromosome 6, affecting multiple genes involved in suppressing the emergence of a tumor. These patients typically have poor prognosis. Another 20 percent of patients have alterations causing chromosomal disorganization and the consequent malfunctioning of several genes and proteins. The bottom line is that for both group of patients it is very difficult to pinpoint which of all the affected genes are actually causing the disease. Clinical Significance Oricchio and her team analyzed the genomes of more than 200 follicular lymphoma patients. Their analyses revealed that Sestrin1 can be harmed by both loss of chromosome 6 or silenced by epigenetic modification in patients. By using specific drugs, it's possible to eliminate this epigenetic block, allowing Sestrin1 to be re-expressed, according to Oricchio. Beyond identifying the Sestrin1 gene as frequently altered in follicular lymphoma patients, the scientists demonstrated the gene is able to suppress tumors in vivo. Investigators also showed that Sestrin1 exerts its anti-tumor effects by blocking the activity of the protein complex mTORC1, well known for controlling protein synthesis as well as acting as a sensor for nutrient or energy changes in the cell, said Oricchio. Premal Lulla, MBBS, Assistant Professor of Medicine in the Center for Cell and Gene Therapy and of Hematology/Oncology at Baylor College of Medicine, Houston, called the findings clinically significant because, outside of the pathognomonic (14,18) alteration, follicular lymphoma cells have a number of other genetic changes such as deletion of 6q or EZH2 gain of function mutations. These alterations are cumulatively seen in almost half of all follicular lymphoma cases.Premal Lulla, MBBS: Premal Lulla, MBBS“However, a pathophysiologic mechanism of how these cooperate to induce and maintain the cancer phenotype remains to be uncovered so as to tailor treatments,” continued Lulla. The identification of loss of Sestrin1 as a key event behind the development of follicular lymphoma is particular important because it helps identify patients who will benefit from new therapies. Indeed, this study shows that the therapeutic efficacy of a new drug currently in clinical trial depends on Sestrin1. Importantly, this dependency can be extended beyond follicular lymphoma to other tumor types. The purpose of this study was to uncover potential targets for future therapies of lymphoma, noted Lulla. “Indeed, the discovery that follicular lymphoma cells can be killed in preclinical models by eliminating epigenetic silencing of Sestrin1 by drug induced inhibition of mutant EZH2 or through direct inhibition downstream mTORC1 with available compounds can lead to the discovery of novel therapies for patients with Sestrin1 alterations. Of course, these would be useful for a large number of follicular lymphoma patients (about 40%) who have silenced Sestrin1, the testing of which could be a predictive biomarker of response to one of these drugs, Lulla noted. Therefore, there's sufficient preclinical rationale to explore the efficacy of these compounds on patients with follicular lymphoma in clinical trials. Still, some questions about the gene remain unanswered.Figure: Disruption of a region in chromosome 6 or epigenetic modifications of the DNA block Sestrin1 expression, which contribute to the development of follicular lymphoma.Continued Investigation “Sestrin1 doesn't play alone,” said Oricchio. Understanding the role of Sestrin1 in follicular lymphoma development is important, she explained, “but we only started to understand its effects on follicular lymphoma pathogenesis.” Moreover, the direct link between Sestrin1 and response to therapy still must be proven in clinical trials, she continued. “While this study certainly provides an insight into the complex pathways responsible in inducing and maintaining lymphoma cells, it remains to be seen if manipulating them as these authors have done in preclinical models would be feasible in humans,” added Lulla. Furthermore, we know that t(14;18) is pathognomonic and pathogenic for follicular lymphoma and, therefore, virtually all follicular lymphoma cells have this alteration, but within the same patient would alterations in Sestrin1 be present in all follicular lymphoma cells as well? Lulla also cautioned that lymphomas are highly chemo-sensitive and the median survival for follicular lymphoma can be over 10 years in select studies. Therefore, to demonstrate clinical efficacy of a novel agent for this disease can be difficult and the success of the novel therapies proposed in this paper would depend upon careful patient selection for future clinical trials. As for the long-term impact, several clinical trials to test epigenetic modifiers (EZH2 inhibitor) are ongoing, and the success of the trials depends on whether the drug is tested “on the right patients,” remarked Oricchio. “We think that Sestrin1 is an important mediator of the response to EZH2 targeted therapies and can be used as a marker to pre-screen patients who will more likely respond to the treatment.” Chuck Green is a contributing writer.

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