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Mar 14

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Duke Researchers Reveal Genetic Causes of Rare, But Lethal HSTL

For the study, human HSTL cells (baseline cells, top image) were modified to knock down one of the most frequent genes mutated in HSTL, SETD2. Cells with SETD2 knockdown were tagged with red fluorescent protein (bottom image) in order to track the changes induced by SETD2 knockdown. (images taken by Matthew McKinney, MD, in the Dave Lab, Duke Cancer Institute)

Led by a team from Duke, an international group of 56 researchers has found new mutations identifying potential treatments and new hope for patients with hepatosplenic T cell lymphoma (HSTL or HSCTL) — one of the deadliest cancers known.

Through whole exome sequencing of 68 human tissue samples from more than 20 institutions, researchers were able to define the genetic landscape of HSTL, including recurrently mutated driver genes and copy number alterations. It is the largest clinical and genetic study ever described in HSTL.

“The top genes that affect these patients are SETD2, STAT5B, STAT3, INO80 and PIK3CD,” said Duke Cancer Institute physician-scientist Sandeep Dave, MD, MS, MBA, the senior and corresponding author of a Cancer Discovery paper that revealed the results of the three-year groundbreaking study in its March 2017 issue. “Not only are they of interest because they give rise to this lethal disease but also because they immediately suggest new therapies.”

Co-first author Matthew McKinney, MD, a hematologist/oncologist who works on the translational aspects of genomics in leukemias and lymphomas and the development of novel therapies, led the biological work for the study. Computational biologist Andrea Moffitt, who recently earned her PhD from the Duke Program in Computational Biology and Bioinformatics, led the computational analysis of the data.

McKinney said that their study suggests that a combination of ruxolitinib phosphate, which targets the JAK-STAT pathway (activated by mutations in the STAT5B and STAT3 genes in HSTL) and idelalisib, which targets the PI 3-kinase pathway (activated by mutations in the PIK3CD gene in HSTL) could be a potentially effective therapy for some HSTL patients.

Ruxolitinib phosphate and idelalisib are small molecule inhibitors or targeted therapies. The signaling pathways they target are critical to cell proliferation and survival in HSTL.

Ruxolitnib phosophate (brand name, Jakafi), according to the National Cancer Institute, works by binding to and inhibiting protein tyrosine kinases JAK 1 and 2, which may lead to a reduction in inflammation and an inhibition of cellular proliferation. The drug is currently only FDA-approved to treat myelofibrosis and the slow-growing blood cancer polycythemia vera — diseases in which the bone marrow produces too many cells.

Idelalisib (brand name, Zydelig), according to NCI, works by inhibiting tumor cell proliferation, motility, and survival and is currently FDA-approved for use alone or with other drugs to treat a recurrence of chronic lymphocytic leukemia (CLL) or Non-Hodgkin lymphoma.

“We have a comprehensive approach to trying to unravel the genetic bases of different cancers,” said Sandeep Dave, MD, MS, MBA, (middle) referring to his lab. “What makes this study so special is that the two people who led the study are in very different specialties. Matt is an oncologist by training and he led the biological work and Andrea led the computational analysis of the data.” (Matthew McKinney, MD, at left, and Andrea Moffitt, PhD, at right)

The research team also discovered the potential for targeting molecular alterations in the SETD2 gene, one of a group of chromatin modifying genes that the researchers identified, including INO80 and ARID1B, which are commonly mutated in HSTL and affect 62 percent of cases.

They experimentally demonstrated that SETD2 acts as a tumor suppressor gene and is the most frequently silenced gene in HSTL.

“We have some indication from this study, and from what we know about other tumors which are SETD2- mutated, about some drugs that could work, but we need to understand more about the biology behind what SETD2 does first,” said McKinney.

Only a few hundred cases of HSTL are diagnosed each year, worldwide, and it affects predominantly patients in their ‘30s; often young men. McKinney, who has seen three HSTL patients referred to his practice at Duke over the past year, said patients almost inevitably succumb to their disease within less than a year of diagnosis.

Unlike other lymphomas, he said, HSTL tends to progress right through first and second line chemotherapy treatments, instead of slowing down or going into remission.

“I suggest high intensity multi-does chemotherapy as a first-line treatment, and possibly bone marrow transplant, for most HTSL patients, and often these do not result in cure of the disease, so we need to embark on studies of molecular targeted therapy such as with ruxolitinib and/or idelalisib,” said McKinney. “As there’s no FDA-approved treatment for this disease; we don’t have a set effective regimen.”

Dave said it’s too early to know just how effective these drugs will be, and because there are so few HSTL patients, these therapies aren’t likely to be tested in clinical trials for the disease.

He said that inevitably some Duke and non-Duke patients will now get treated off-label with these drugs, and he’s hoping the data in the study will give insurers a rationale for covering these experimental drugs.

“Probably the biggest obstacle for patients is getting insurance companies to pay for these drugs,” said Dave.

His lab set up an online HSTL forum to share information about HSTL and encourage patients, their caregivers, and physicians to communicate their treatment experiences and donate patient tissue samples.

“In this way, we hope to track how the experimental therapies are working,” said Dave. “It could be greatly beneficial to other patients and our continued research.”

Researchers across DCI are taking a close look at molecular mutations across cancers to see what’s targetable. Moving forward, the Dave Lab, which focuses on genetic underpinnings of cancer, is continuing to study the risk factors for and molecular features of HTSL, particularly in patients who have inflammatory bowel disease, Crohn’s disease, rheumatoid arthritis, and other autoimmune diseases. Dave said the immune-suppression drugs taken to combat these conditions is a risk factor for HSTL, and the use of those drugs is rising.

The lab is now trying to dissect some of the mechanisms of the most common mutations for HSTL through transgenic mouse models.

From Duke, hematologic oncologist Anne W. Beaven, MD, and professor of immunology and molecular genetics Yuan Zhuang, PhD — both with DCI — as well as Dave Lab members lead bioinformatician Anupama Reddy, PhD, staff scientist Guojie Li, PhD, post-doctoral fellow Jyotishka Datta, bioinformatics specialist Deepthi Rajagopalan, lab manager Cassandra Love, MS, and graduate students Nicholas Davis and Jenny Zhang, also contributed to this research and paper published in Cancer Discovery.  The full list of authors, including from other institutions, are listed here.  

Permanent link to this article: https://sites.duke.edu/dukecancerinstitute/duke-researchers-reveal-genetic-causes-of-rare-but-lethal-hstl/

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