PDXP

A low vitamin B6 level has negative effects on brain performance. A research team has now found a way to delay the degradation of the vitamin. Vitamin B6 is important for brain metabolism. Accordingly, in various mental illnesses, a low vitamin B6 level is associated with impaired memory and learning abilities, with a depressive mood, and even with genuine depression. In older people, too little vitamin B6 is linked to memory loss and dementia. Although some of these observations were made decades ago, the exact role of vitamin B6 in mental illness is still largely unclear. What is clear, however, is that an increased intake of vitamin B6 alone, for example in the form of dietary supplements, is insufficient to prevent or treat disorders of brain function. Publication in eLife A research team from Würzburg University Medicine has now discovered another way to increase vitamin B6 levels in cells more effectively: namely by specifically inhibiting its intracellular degradation. Antje Gohla, Professor of Biochemical Pharmacology at the Department of Pharmacology and Toxicology at Julius-Maximilians-Universität Würzburg (JMU), is responsible for this. Other participants come from the Rudolf Virchow Center for Integrative and Translational Bioimaging at JMU, the Leibniz-Forschungsinstitut für Molekulare Pharmakologie-FMP Berlin and the Institute for Clinical Neurobiology at Würzburg University Hospital. The team has now published the results of their investigations in the scientific journal eLife. Enzyme Blockade Improves Learning Ability "We were already able to show in earlier studies that genetically switching off the vitamin B6-degrading enzyme pyridoxal phosphatase in mice improves the animals' spatial learning and memory capacity," explains Antje Gohla. In order to investigate whether such effects can also be achieved by pharmacological agents, the scientists have now looked for substances that bind and inhibit pyridoxal phosphatase. With success: "In our experiments, we identified a natural substance that can inhibit pyridoxal phosphatase and thus slow down the degradation of vitamin B6," explains the pharmacologist. The working group was actually able to increase vitamin B6 levels in nerve cells that are involved in learning and memory processes. The name of this natural substance: 7,8-Dihydroxyflavone. New Approach for Drug Therapy 7,8-Dihydroxyflavone has already been described in numerous other scientific papers as a molecule that can improve learning and memory processes in disease models for mental disorders. The new knowledge of its effect as an inhibitor of pyridoxal phosphatase now opens up new explanations for the effectiveness of this substance. This could improve the mechanistic understanding of mental disorders and represent a new drug approach for the treatment of brain disorders, the scientists write in their study. The team also considers it a great success that 7,8-Dihydroxyflavone has been identified as an inhibitor of pyridoxal phosphatase for the first time -- after all, this class of enzymes is considered to be particularly challenging for drug development. A Long Way to a Drug When will people benefit from this discovery? "It's too early to say," explains Marian Brenner, a first author of the study. However, there is much to suggest that it could be beneficial to use vitamin B6 in combination with inhibitors of pyridoxal phosphatase for various mental disorders and neurodegenerative diseases. In a next step, Gohla and her team now want to develop improved substances that inhibit this enzyme precisely and highly effectively. Such inhibitors could then be used to specifically test whether increasing cellular vitamin B6 levels is helpful in mental or neurodegenerative diseases.

Volastra Chief Executive Officer Charles Hugh-Jone Bristol Myers Squibb Company forged an oncology drug discovery and development deal valued at more than $1 billion with Volastra Therapeutics. Volastra Chief Executive Officer Charles Hugh-Jones/Courtesy Volastra Therapeutics Hot off the heels of its milestone approval for the unique checkpoint inhibitor Opdualag , Bristol Myers Squibb Company forged an oncology drug discovery and development deal valued at more than $1 billion with Volastra Therapeutics . BMS will leverage Volastra’s proprietary CINtech platform to identify CIN-related, synthetic lethal targets as drug candidates. In its announcement, New York-based Volastra noted that synthetic lethality is a well-established genetic approach to target discovery. The approach involves the exploitation of the vulnerabilities in the cells of cancerous tumors in order to safely induce cell death while sparing normal cells. Volastra noted that its pre-clinical research has shown that synthetical lethal approaches can be particularly effective in tumors with high levels of CIN, which has been identified as a key driver of metastatic cancer. Volastra is developing proprietary computational and experimental approaches to understand CIN biology and drive drug discovery. The company’s CINtech platform marries proprietary imaging technologies, model cell line systems and computational analytics. Rupert Vessey, executive vice president of research & early development at BMS, expressed excitement about the collaboration with Volastra and the company’s chromosomal instability targeting platform. Vessey said new therapies targeting CIN have the potential to enhance treatment selectivity and improve patient outcomes. The two companies are keeping the oncology targets close to the vest. Under the agreement terms, Volastra is expected to conduct research activities through the selection of developmental candidates. From there, BMS may take on all subsequent development, regulatory and commercialization activities. Volastra stands to make a significant amount of money from the partnership but the financial terms are heavily weighted on the back end of the deal. Volastra will receive an upfront payment of $30 million and stands to make an additional $1.1 billion from potential development, regulatory and commercial milestone payments. Volastra will also be eligible for royalties on any sales. Volastra Chief Executive Officer Charles Hugh-Jones, a Pfizer veteran, said his company has a significant understanding of chromosomal instability, which he called the “Achilles heel” of cancer. The oncology expertise of BMS combined with Volastra’s platform is an ideal partnership to develop and advance novel therapies, he said. “Through this collaboration, Volastra will apply our innovative platform towards the creation of effective CIN-targeted medicines. We look forward to working together with Bristol Myers Squibb to transform cancer treatment,” Hugh-Jones said in a statement. In addition to BMS, Volastra has also partnered with Dewpoint Therapeutics to discover novel molecules capable of blocking immuno-suppressive signaling in CIN-high tumors. The company also entered into a big data partnership with Microsoft to develop algorithms capable of identifying markers that correlate with tumor metastatic behaviors. Oncology is a key focus for BMS. While the company celebrated the regulatory win for its LAG-3-aimed Opdualag for melanoma, the company also saw a setback in Melanoma with the failure of the Phase III PIVOT IO-001 study. That trial saw the pairing of Nektar Therapeutics’ immunotherapy drug bempegaldesleukin in combination with BMS’ anti-PD-1 drug Opdivo compared to Opdivo alone in metastatic melanoma. As BioSpace previously reported , the trial failed to meet two of the endpoints: progression-free survival and objective response rate. Featured Jobs on BioSpace

Volastra Chief Executive Officer Charles Hugh-Jone The New York-based company inked a deal with Microsoft to develop unique digital pathology tools for oncology and also announced its seed funding round was extended from $12 million to $44 million. CEO Charles Hugh-Jones (Volastra) Oncology startup Volastra Therapeutics is having a busy morning. The New York-based company inked a deal with Microsoft to develop unique digital pathology tools for oncology and also announced its seed funding round was extended from $12 million to $44 million. The additional funds will support the continued build-out of Volastra’s technology platform, which exploits unique insights into chromosomal instability (CIN) to rapidly identify and validate novel targets to block metastasis. Pfizer veteran Charles Hugh-Jones, chief executive officer of Volastra, said the financing places the company in a position of strength that will allow it to advance its “bold vision to change the treatment paradigm for patients with metastatic cancers.” Volastra noted that more than 350,000 people in the United States alone are diagnosed with metastatic cancer. Of those patients, less than one-third respond to targeted or immuno-therapies, which makes metastasis one of the most pressing unsolved challenges in cancer. The company uses an extensive library of organoids developed from metastatic cancer samples to understand the spread of tumors and develop therapeutic strategies to target chromosomal instability during the process of metastasis. This platform enables Volastra to perform rigorous target validation, to advance first-in-class clinical candidates, and to identify biomarkers to stratify patients for clinical trials, according to the company. The seed funding extension was supported by new investors Vida Ventures and Catalio Capital Management. They joined with other investors that include Polaris Partners, Droia Ventures, ARCH Venture Partners, and Quark Venture. “The support of our new and existing investors reflects the increasing interest around CIN as a core driver in cancer biology,” Hugh-Jones, who joined New York-based Volastra as CEO last year after serving as chief medical officer at Allergan, said in a statement. CIN was identified by Volastra’s scientific founders as a key driver of metastatic cancer. The company is developing proprietary computational and experimental approaches to understand CIN biology and drive drug discovery. Among Volastra’s tools is a proprietary technology suite to bulk-measure and exploit vulnerabilities in chromosomally unstable cancer cells, according to the company. Since its launch last year , Volastra has not only been busy developing its technology, but also forging relationships with other companies that can help advance oncology research. Last month, the company announced a partnership with Dewpoint Therapeutics to discover novel molecules capable of blocking immuno-suppressive signaling in CIN-high tumors. In CIN-high cells, chronic pro-inflammatory signaling can suppress the intrinsic immune response, promoting treatment resistance and progression and driving metastasis, the companies said in a joint statement. The Volastra-Dewpoint collaboration is focused on selectively blocking the formation of a condensate in which this signaling occurs. This morning, the partnership with Microsoft was announced. Volastra will harness the big data capabilities of Microsoft and develop algorithms that identify markers correlating with tumor metastatic behaviors. Volastra said the collaboration will develop automated machine learning tools capable of rapidly and accurately integrating insights across multiple datasets, including pathology slides and three-dimensional tumor-derived organoids. Desney Tan, Managing Director of Microsoft Health Futures said advanced computation offers “tremendous promise” in the fields of medical diagnostics and drug discovery. “The collaboration with Volastra will lead to potential advances in the development of therapies to prevent and treat cancer metastasis,” said Tan. “We look forward to continued collaboration with Volastra to deliver solutions for the computational life sciences community.”