Genetic Engineering & Biotechnology News

JAN15 2018

Genetic Engineering & Biotechnology News (GEN) is the world's most widely read biotech publication. It provides the R&D community with critical information on the tools, technologies, and trends that drive the biotech industry.

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14 | JANUARY 15, 2018 | | Genetic Engineering & Biotechnology News therapy, especially when exploited in tandem with the administration of other medications, 4SC AG's Chief Development Officer Frank Hermann, M.D., told GEN. Inhibiting an Epigenetic Eraser Epigenetic inhibition could be a viable approach for patients with the blood cancer acute myeloid leukemia (AML). A hallmark of the disease is the proliferation of cells that have not completely matured. These cells, which typically turn into white blood cells to fend off infection, don't differentiate. In- stead, they stay in a stem cell−like state. Research has shown that lysine-specific histone demethylase 1 (LSD1) plays an es- sential role in the self-renewal of these "leu- kemic stem cells," Incyte principal investi- gator Sang Hyun Lee, Ph.D., tells GEN. Building on this finding, Dr. Lee and col- leagues developed an LSD1 inhibitor called INCB059872, which spurs myeloid cell differentiation. That helps to eradicate the cells that are at the root of the leukemia, something conventional therapies can't do, Dr. Lee says. Preclinical studies also suggest INCB059872 could help combat small-cell lung cancer and Ewing Sarcoma, and clini- cal trials are currently underway to test the drug's efficacy in patients with sickle-cell disease, as well as its safety in patients with advanced malignancies. What could be truly exciting, Dr. Lee notes, is the combination of LSD1 inhibitors with antibodies that block programmed cell death-1 (PD-1), a cell surface receptor that keeps the immune system in check. Together, the one-two punch could spur the body's own immune system to attack cancer cells. Modifying Other Epigenetic Markers Aside from HDMs such as LSD1, HDACs have become cancer targets. At 4SC AG, researchers are working on 4SC- 202, an inhibitor of HDAC1, HDAC2, and HDAC3. Preclinical tests show that the in- hibitor can change the microenvironment of a tumor by increasing populations of antitu- mor immune cells in the area. 4SC-202 also appears to increase the expression of tumor- associated antigens and immunomodulatory molecules in cancer cell lines. Specifically, CD8+ cells, also known as cytotoxic T cells, burst onto the scene, while other immune system suppressor cells drop off, Dr. Her- mann tells GEN. Like the developers of LSD1 combination therapies, 4SC AG researchers are pairing an epigenetic drug, in this case an HDAC in- hibitor, with immunotherapies. Inactivating immune system checkpoints such as PD-1 and treating cells with 4SC-202 can inhibit tumor growth. 2 A clinical trial to test the efficacy of combining the epigenetic cancer drug with pembrolizumab, a humanized an- tibody that inhibits PD-1, is currently under- way. Together, the drugs appear to prevent cancer cells from evading detection. "I think the future of oncology, in terms of treating solid tumors, will be these com- bination therapies," Dr. Hermann says. Homing In on HDAC6 But the focus is not entirely on HDACs that act on histones. HDAC6, for example, can deacetylase tubulins, proteins that join together to form microtubules. This thread- like material is a staple of the cell cytoplasm and helps transport genetic material to cell nuclei during mitosis. Microtubules help cancer cells move, which is why tubulins are targets for current cancer drugs such as Taxol (paclitaxel). Because HDAC6 is associated with tubu- lin, it has become a prime target in cancer therapy. Studies show HDAC6 is overex- pressed in solid tumors. 3 It plays a role in the movement and survival of tumor cells. Researchers are looking for ways to in- hibit HDAC6, preventing it from deacetylas- ing tubulins. One inhibitor being developed is Karus Therapeutics' KA2507. In preclini- cal studies, this inhibitor reduced the ex- pression of PD-1, causing tumor suppressor genes to switch on. 4 Tumor cell division was inhibited, and apoptosis began in unhealthy cells overexpressing HDAC6. Another HDAC6 inhibitor Karus is working on is KA2237, which inhibits pri- mary tumor growth and metastasis. Ka- rus' COO and CSO Stephen Shuttleworth, Ph.D., reported in 2016 that the inhibitors could work in combination with one an- other to treat cancer. 4 The co-therapy tactic OMICS Feature Epigenetic Drugs: Team Players in Combo Therapies Continued from page 1 Accelerate your research with innovative nucleic acid QC solutions from Advanced Analytical Technologies, Inc. Simplify your workflows, no matter which application you use. Our instruments automate quality and quantity analysis for sample QC— so you can keep your focus on discovery. See how our full range of instruments can improve any QC process. BRING THE BIGGEST BREAKTHROUGHS INTO FOCUS. R

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