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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Genetic Engineering & Biotechnology News | | JANUARY 15, 2018 | 15 could potentially become important clinical- ly, and could be used to overcome resistance mechanisms in both solid and hematological cancers. Both aforementioned investigation- al candidates from Karus are being tested in clinical trials. Moving beyond Cancer Alan Kozikowski, Ph.D., founder and CEO of StarWise Therapeutics, is also working on HDAC6 inhibitors. He and col- leagues have developed several candidates, some of which are being tested by pharma- ceutical companies such as Celgene. One of the candidates is ACY-1215 (Ricolinostat). It is, in combination with other drugs, cur- rently in clinical trials for the treatment of multiple myeloma. There's also Tubastatin A, which, in a recent study, seemed to force glioblastoma cells toward self-destruction. 5 In another experiment, the drug candidate showed promise in treating Alzheimer's disease. 6 But Dr. Kozikowski seems most excited about StarWise-100, a new drug candidate that could be a therapeutic option to treat Charcot-Marie-Tooth disease, an inherited nerve disorder characterized by the loss of muscle use in the legs and loss of sensation to touch. The disorder causes patients to trip, sprain their ankles, and feel the tingling known as "pins and needles." Pointing to preclinical test results (which are still unpublished at time of print), Dr. Kozikowski asserts that animals with the dis- ease that were treated with StarWise-100 re- gained sensory abilities and movement. Star- Wise is now trying to "fast track" the drug for studies to treat other conditions, such as Rhett syndrome. Why might an HDAC6 inhibitor work for these diseases? Because of mitochon- dria, Dr. Kozikowski suggests. Acetylation of tubulin creates threads that facilitate the movement of mitochondria, specifically in hippocampal neurons. If tubulin is deacety- lated, however, mitochondria don't move so smoothly, interrupting nerve cell activity and, ultimately, muscle movement. With that in mind, Dr. Kozikowski is collaborating with a group of researchers to develop novel HDAC6 inhibitors to treat glioblastoma, Al- zheimer's disease, and other central nervous system diseases. But, Dr. Kozikowski says, there's some- thing really important to keep in mind when designing HDAC inhibitors: the drugs are capable of damaging genetic information and, as a result, could be a source for second- ary cancers. "You don't want to cause a patient to de- velop tumors while trying to cure [his or her] neurodegenerative disease," Dr. Kozikowski emphasizes. "What we need to do is make drugs safer and better." 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Discover the difference of a faster turnaround time and full-service solution. Discover the difference of BD. OMICS Dr. Kozikowski says there's something really important to keep in mind when designing HDAC inhibitors: the drugs are capable of damaging genetic information and, as a result, could be a source for secondary cancers. References 1. S. Sharma et al., "Epigenetics in Cancer," Carcino- genesis 31(1), 27–36 (January 1, 2010), https://doi. org/10.1093/carcin/bgp220. 2. F. Hermann, "Clinical Development of 4SC-202, A Combined Epigenetic Inhibitor of HDAC Class I and LSD1, to Overcome Anti-PD-1 Refractoriness and Increase Efficacy of Checkpoint Inhibition," J. Clin. Oncol. 35(15_suppl), doi: 10.1200/JCO.2017.35.15_ suppl.e14096. 3. G.I. Aldana-Masangkay and K.M. Sakamoto, "The Role of HDAC6 in Cancer," J. Biomed. Bio- technol. (published online November 7, 2010), doi:10.1155/2011/875824. 4. S.J. Shuttleworth, "Abstract 3996: KA2237 and KA2507: Novel, Oral Cancer Immunotherapeutics Targeting PI3K-p110β/p110δ and HDAC6 with Single-Agent and Combination Activity," Proceed- ings: AACR 107th Annual Meeting 2016, (April 16–20, 2016, New Orleans, LA, published July 2016), doi:10.1158/1538-7445.AM2016-3996. 5. Z. Wang et al., "HDAC6 Promotes Cell Prolifera- tion and Confers Resistance to Temozolomide in Glioblastoma," Cancer Lett. 379(1), 134–142 (August 28, 2016). 6. L. Zhang et al., "Tubastatin A/ACY-1215 Improves Cognition in Alzheimer's Disease Transgenic Mice," J. Alz. Dis. 41(4), 1193–1205 (2014).

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