KAT8

A new study has identified 17 genetic variants that may influence Alzheimer's disease risk, putting researchers one step closer to uncovering biological pathways to target for future treatment and prevention. Identifying genetic variants and the role they play in predisposing people to Alzheimer's disease can help researchers better understand how to treat the neurodegenerative condition for which there is currently no cure. A new study led by Boston University School of Public Health (BUSPH) and UTHealth Houston School of Public Health has identified several genetic variants that may influence Alzheimer's disease risk, putting researchers one step closer to uncovering biological pathways to target for future treatment and prevention. Published in the journal Alzheimer's & Dementia: The Journal of the Alzheimer's Association, the study utilized whole genome sequencing and identified 17 significant variants associated with Alzheimer's disease in five genomic regions. This data enables researchers to pinpoint rare and important genes and variants, building upon genome-wide association studies, which focus only on common variants and regions. The findings underscore the value of whole genome sequencing data in gaining long-sought insight into the ultimate causes and risk factors for Alzheimer's disease, which is the fifth leading cause of death among people 65 and older in the United States. As the most common form of dementia, Alzheimer's disease currently affects more than 6 million Americans and that number is expected to skyrocket to nearly13 million by 2050. "Prior genome-wide association studies using common variants have identified regions of the genome, and sometimes genes, that are associated with Alzheimer's disease," says study co-senior author Dr. Anita DeStefano, professor of biostatistics at BUSPH. "Whole genome sequence data interrogates every base pair in the human genome and can provide more information about which specific genetic change in a region may be contributing to Alzheimer's disease risk or protection." For the study, the researchers conducted single variant association analyses and rare variant aggregation association tests using whole genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP), a genetics initiative that the National Institutes of Health developed in 2012 as part of the National Alzheimer's Project Act's goal to treat and prevent the disease. The ADSP data include more than 95 million variants among 4,567 participants with or without the disease. Among the 17 significant variants that were linked to Alzheimer's disease, the KAT8 variant was one of the most notable, as it was associated with the disease in both the single and rare variant analyses. The researchers also found associations with several rare TREM2 variants. "By using whole genome sequencing in a diverse sample, we were able to not only identify novel genetic variants associated with Alzheimer's disease risk in known genetic regions, but also characterize whether the known and novel associations are shared across populations," says study co-lead and corresponding author Dr. Chloé Sarnowski, assistant professor in the Department of Epidemiology at UTHealth Houston School of Public Health. The ADSP includes ethnically diverse participants, and the population-specific assessments focused on White/European-ancestry, Black/African-American, and Hispanic/Latino subgroups, as well as a multi-population meta-analysis. Historically, Black and and Latino populations have been underrepresented in genetic studies of Alzheimer's disease despite having a higher prevalence of the disease than other ethnic groups. "Including participants that represent diverse genetic ancestry and diverse environments in terms of social determinants of health is important to understanding the full spectrum of Alzheimer's disease risk, as both the prevalence of the disease and the frequencies of genetic variants can differ among populations," says Dr. DeStefano. The sample sizes in the population-specific analyses were small, so the team had limited ability to detect associations, she says, "but we replicated known population differences for the APOE gene, which is one of the best-known and strongest risk genes for Alzheimer's disease." In future studies, the researchers hope to examine the population-specific variants they identified in much larger sample sizes, as well as explore how these variants affect biological functioning. "We are currently working on expanding this research to be able to use whole genome sequencing with larger sample sizes in the ADSP to be able to look at the full array of genetic variants, not only within known Alzheimer's disease genetic regions, but across the whole genome," says co-senior author Dr. Gina Peloso, associate professor of biostatistics at BUSPH. The study was also co-led by Yanbing Wang while she was a PhD student in biostatistics at BUSPH. It was funded by the National Institute on Aging under Award Numbers U01 AG058589 and U01 AG068221.

SAN FRANCISCO, Oct. 12, 2023 (GLOBE NEWSWIRE) -- Olema Pharmaceuticals, Inc. (“Olema” or “Olema Oncology,” Nasdaq: OLMA), a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of targeted therapies for women’s cancers, today announced new preclinical data regarding the discovery of novel compounds targeting KAT6, an epigenetic target that is dysregulated in breast and other cancers. These data will be presented today at a poster session at the 2023 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics (ANE 2023) in Boston, Massachusetts. The poster, titled “The discovery of potent KAT6 inhibitors that demonstrate anti-tumor activity in preclinical models of ER+ breast cancer”, describes the discovery and preclinical characterization of orally bioavailable, potent KAT6A and KAT6B-selective inhibitors developed by Olema in collaboration with Aurigene Oncology. The poster highlights that: Olema KAT6 compounds were selective and potent against KAT6A and KAT6B (<20 nM IC50) with >250-fold selectivity over other KAT family members, including the essential genes KAT5 and KAT8. In KAT6-amplified and overexpressing breast cancer cell lines, Olema KAT6 compounds strongly inhibited cell proliferation whereas KAT6-low cell lines were insensitive to the compounds. Olema KAT6 inhibitor compounds caused dose-dependent tumor growth inhibition and tumor regression comparable to or better than a positive-control patented KAT6 inhibitor. Olema KAT6 inhibitor compounds are orally bioavailable with desirable pharmacokinetics. Olema KAT6 inhibitor compounds demonstrate histone target engagement and efficacy, as well as synergism with palbociclib or palazestrant (OP-1250). “The dysregulation of KAT6 activity is observed across breast and other cancers, and inhibition of the KAT6 histone acetyltransferase enzyme reduces breast cancer cell proliferation through downregulation of genes involved in estrogen receptor signaling and other signaling pathways,” said David C. Myles, Ph.D., Chief Discovery and Non-Clinical Development Officer of Olema Oncology. “As noted in our poster today, the KAT6 inhibitors we are developing have demonstrated attractive potency and selectivity at inhibiting KAT6-amplified estrogen-receptor-positive (ER+) breast cancer cells, both wild-type and ESR1 mutated. Additionally, the compounds demonstrated synergistic activity in combination with CDK4/6 inhibitors and endocrine agents such as palazestrant (OP-1250).” Olema’s KAT6 program has been developed in collaboration with Aurigene Oncology. A copy of the poster is available on Olema’s website under the Science section. About Olema Oncology Olema Oncology is a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of targeted therapies for women’s cancers. Olema’s lead product candidate, palazestrant (OP-1250), is a proprietary, orally-available small molecule with dual activity as both a complete estrogen receptor (ER) antagonist (CERAN) and a selective ER degrader (SERD). It is currently being evaluated both as a single agent in an ongoing Phase 2 clinical trial, and in combination with CDK4/6 inhibitors (palbociclib and ribociclib) and a PI3Ka inhibitor (alpelisib), in patients with recurrent, locally advanced or metastatic ER-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. Palazestrant has been granted FDA Fast Track designation for the treatment of ER+/HER2- metastatic breast cancer that has progressed following one or more lines of endocrine therapy with at least one line given in combination with a CDK4/6 inhibitor. Olema is headquartered in San Francisco and has operations in Cambridge, Massachusetts. For more information, please visit us at , or follow us on Twitter and LinkedIn. Forward Looking Statements Statements contained in this press release regarding matters that are not historical facts are “forward-looking statements” within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. Words such as “anticipate,” “expect,” “will,” “may,” “goal,” “potential” and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) are intended to identify forward-looking statements. These statements include those related to Olema’s preclinical program, including the potential beneficial characteristics of its KAT6 inhibitor compounds and its applicability to breast and other cancers, and the potential synergistic activity of Olema’s KAT6 inhibitor compounds with CDK4/6 inhibitors or palazestrant (OP-1250). Because such statements deal with future events and are based on Olema’s current expectations, they are subject to various risks and uncertainties, and actual results, performance or achievements of Olema could differ materially from those described in or implied by the statements in this press release. These forward-looking statements are subject to risks and uncertainties, including, without limitation, those discussed in the section titled “Risk Factors” in Olema’s Quarterly Report on Form 10-Q for the quarter ended June 30, 2023, and future filings and reports that Olema makes from time to time with the U.S. Securities and Exchange Commission. Except as required by law, Olema assumes no obligation to update these forward-looking statements, including in the event that actual results differ materially from those anticipated in the forward-looking statements. Contact: Geoffrey Mogilner, Vice President, Investor Relations and Communications ir@olema.com