AR x GR

New research sheds light on the significance of the glucocorticoid receptor in drug-resistant prostate cancer, showing that the development of drug resistance could be prevented by limiting the activity of coregulator proteins. New research from the University of Eastern Finland sheds light on the significance of the glucocorticoid receptor in drug-resistant prostate cancer, showing that the development of drug resistance could be prevented by limiting the activity of coregulator proteins. Glucocorticoids regulate vital biological processes by affecting gene encoding through a DNA-binding transcription factor, namely the glucocorticoid receptor. The activity of the glucocorticoid receptor is made extensive use of in medicine because glucocorticoids have a strong anti-inflammatory effect. For this reason, synthetic glucocorticoids are one of the most prescribed drugs in the world. They are used to treat inflammatory diseases, such as rheumatoid arthritis, and as adjuvant therapy for cancer patients to alleviate the side effects of cancer therapy. In blood cancer, glucocorticoids are important drugs that limit the growth of cancer cells. However, recent studies have shown that the glucocorticoid receptor also has an oncogenic, or cancer-promoting, effect in cancers like breast and prostate cancer. In prostate cancer, the glucocorticoid receptor can replace the activity of the androgen receptor, which is main oncogenic factor in this cancer, when its activity is inhibited by drug therapy. Thus, glucocorticoids help prostate cancer develop resistance to drug therapy. "Due to these drug resistance and cancer-promoting effects, it is important to study how the glucocorticoid receptor functions on the cellular and molecular level in cancer," Academy Research Fellow, Docent Ville Paakinaho of the University of Eastern Finland notes. The Paakinaho Lab has published two recent genome-wide deep sequencing studies on the subject. The first, published in Nucleic Acids Research, explored how the glucocorticoid receptor replaces the androgen receptor on the molecular level. "This study showed that the glucocorticoid receptor can only use regulatory regions that are already active in prostate cancer cells," says Doctoral Researcher Laura Helminen of the University of Eastern Finland. In other words, glucocorticoid receptor-mediated drug resistance emerges through these regulatory regions, and by affecting the activity of these areas, the harmful effects of glucocorticoids in prostate cancer could be prevented. Bioinformatics analyses indicated the pioneer transcription factor FOXA1 as one possible target. FOXA1 is known to have cancer-promoting properties, which is why the researchers assumed that inhibiting its activity would limit the development of glucocorticoid receptor-mediated drug-resistant prostate cancer. Surprisingly however, the effect was exactly the opposite: inhibiting the activity of FOXA1 further increased the activity of the glucocorticoid receptor -- and the development of drug resistance. This is because FOXA1 was found to be involved in the silencing of the glucocorticoid receptor gene, and this is what increased its activity when FOXA1 was inhibited. "Research often reveals the unexpected, and that's part of its charm," Paakinaho says. The activity of the glucocorticoid receptor in regulatory regions can, however, be influenced in drug-resistant prostate cancer through an alternative pathway. Coregulator proteins were identified as an alternative target through which the glucocorticoid receptor affects the regulation of gene expression. These proteins include EP300 and CREBBP. Several pharmaceutical companies are developing small-molecule inhibitors targeting these proteins, and some are already being studied in patients. In another study by the Paakinaho Lab, the researchers explored ways to inhibit glucocorticoid receptor-mediated effects by inhibiting coregulator proteins. These findings were reported in Cellular and Molecular Life Sciences. "Silencing the EP300 and CREBBP proteins with a small-molecule inhibitor clearly prevented the activity of the glucocorticoid receptor in prostate cancer cells," Project Researcher Jasmin Huttunen of the University of Eastern Finland says. This allowed the growth of drug-resistant prostate cancer cells to be inhibited. Furthermore, the researchers found that silencing EP300 and CREBBP also effectively inhibited the activity of the androgen receptor especially in prostate cancer cells that have an amplification of the androgen receptor gene. This amplification is found in up to half of patients with advanced prostate cancer. Surprisingly, the EP300 and CREBBP inhibitor also inhibited the activity of FOXA1, while still preserving its ability to silence the expression of the glucocorticoid receptor gene. By using the EP300 and CREBBP inhibitor, it was possible to block the activity of FOXA1 without the development of glucocorticoid receptor-mediated drug resistance. Ultimately, inhibiting the activity of both the androgen and the glucocorticoid receptor was found to be primarily due to the limitation of FOXA1 activity. The study suggests that treatment targeting coregulator proteins could also be effective in untreated prostate cancer. The studies were funded by the Research Council of Finland, the Sigrid Jusélius Foundation, and the Cancer Foundation Finland.

NEW YORK and SHANGHAI, China, Feb. 05, 2024 (GLOBE NEWSWIRE) -- Yiviva, a clinical-stage, platform biotechnology company developing systems biology medicines to treat aging-related diseases, signed a memorandum of understanding (MOU) with AstraZeneca China to establish a research and development collaboration at AstraZeneca’s Innovation Campus (iCampus) in Chengdu, China. The signing ceremony took place at the 2023 China International Import Expo (CIIE) at the National Exhibition and Convention Center in Shanghai. To address global unmet medical needs, Together Yiviva and AstraZeneca China will jointly build platforms for scientific research transformation and industrial development led by academicians and experts with the aim to modernize botanical medicines in accordance with new regulatory pathways for botanical medicines by the United States Food and Drug Administration (FDA) and China National Medical Products Administration (NMPA). “2023 marks the 30th anniversary of AstraZeneca in China. In collaboration with the Chengdu government and Chengdu High-Tech Industrial Zone (CDHT), AstraZeneca is establishing a modern healthcare development platform integrating traditional Chinese medicine and Western medicine. At CIIE, AstraZeneca announced plans to further globalize Chinese medicine. Our strategic partnership with Yiviva, will advance our blueprint for how to develop innovative medicines inspired by Chinese medicine,” remarked Lily Zhu, Vice President of AstraZeneca China and Head of DCI and CSE. “Disease knows no borders. By bringing together the knowledge and best practices of Western and Eastern Medicine, WE Medicine, we can learn from ancient wisdom to develop future medicines. Together with AstraZeneca China’s expertise, ecosystem, and resources, and Yiviva’s team, platform technologies, and pipeline, we can pioneer a new paradigm for systems biology drug development to address global unmet medical needs,” said Peikwen Cheng, Co-Founder and CEO of Yiviva. About Yiviva’s Platforms and Pipeline in Oncology Yiviva’s STAR (signal transduction, activity and response) drug discovery platform accelerates the identification of botanical therapeutics that influence immune function, inflammatory responses, cell growth, metabolic functions, and hormone activity. Through STAR, Yiviva can design sophisticated multi-target drugs that map to complicated disease biology. Yiviva has discovered six first-in-class drug candidates to treat cancer and inflammatory diseases. Yiviva applies patented, mechanism-based quality control linked to biological activity to manufacture batch-to-batch consistent drug product that satisfies established regulatory requirements for complex products. Yiviva’s lead candidate drug YIV-906 is a proprietary extract of 4 medicinal plants, inspired by an 1800-year-old traditional Chinese medicine formula. YIV-906 acts as an immunomodulator in the tumor microenvironment, turning cold tumors hot and potentiating anti-tumor activity for chemotherapies, immunotherapies, cell therapies, or radiation therapies; and acts as a cytoprotector in the gastrointestinal tract, reducing non-hematological toxicities and speeding up damaged tissue recovery. Yiviva has conducted 8 early-stage clinical trials in solid tumors (hepatocellular carcinoma, pancreatic cancer, colorectal cancer, and rectal cancers), with promising data suggesting that YIV-906 could prolong survival and improve quality of life. Yiviva recently recruited its last-patient-in in a first-line, randomized, double-blinded Phase 2b study of sorafenib plus YIV-906 in the treatment of hepatocellular carcinoma patients with hepatitis B. The CALM study is a multi-regional trial in the United States, Mainland China, Hong Kong, and Taiwan and expects a data readout in 2024. Yiviva recently published preclinical data conducted at Yale University about its novel therapeutic YIV-818-A to treat prostate cancer. YIV-818-A acts through multiple mechanisms, including androgen receptor downregulation, glucocorticoid receptor inhibition, epigenetic regulation and could help overcome drug resistance to prostate cancer and could enhance apalutamide, darolutamide, or enzalutamide efficacy. About Yiviva Yiviva is a clinical stage, platform biotechnology company developing systems biology medicines to prevent, treat, and/or cure aging-related diseases, including cancer and inflammatory diseases. The company was launched with Yale University and Henry Bronson Professor of Pharmacology and Medicine Yung-Chi Cheng as co-founders, with teams in the United States and Greater China. Yiviva’s investors include the National Foundation for Cancer Research and the Asian Fund for Cancer Research. For further information, please visit https://yiviva.com. About AstraZeneca AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in Oncology, Rare Diseases and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on social media @AstraZeneca. Contact:Email: hello@yiviva.com A photo accompanying this announcement is available at https://www.globenewswire.com/NewsRoom/AttachmentNg/8d78fdf0-e819-4a98-abe1-3944978b9ad8

Lead program ORIC-101 on track for two initial data readouts in 2021 Three IND/CTA filings for ORIC-533, -944, and -114 expected in 2021 Cash, Cash Equivalents and Investments of $293.6 million expected to fund current operations into second half of 2023 SOUTH SAN FRANCISCO, Calif. and SAN DIEGO, March 23, 2021 (GLOBE NEWSWIRE) -- ORIC Pharmaceuticals, Inc. (Nasdaq: ORIC), a clinical stage oncology company focused on developing treatments that address mechanisms of therapeutic resistance, today reported financial results and operational updates for the quarter and year ended December 31, 2020. “2020 was a transformational year for ORIC during which we significantly grew and advanced our pipeline, expanded the team, and strengthened the balance sheet,” said Jacob Chacko, M.D., president and chief executive officer. “The progress we made in 2020 has positioned us for a dynamic 2021, with our first data from two ongoing trials of our lead program ORIC-101 and three IND/CTAs for our other product candidates, a significant amount of development activity for a company at our stage.” Fourth Quarter 2020 and Other Recent Highlights ORIC-101: Glucocorticoid Receptor (GR) Antagonist ORIC-101 is a potent and selective GR antagonist, with two distinct mechanisms of action being evaluated in two Phase 1b trials in combination with: (1) Abraxane (nab-paclitaxel) in advanced or metastatic solid tumors and (2) Xtandi (enzalutamide) in metastatic prostate cancer. Completed the Part I dose escalation portion of ORIC-101 in combination with nab-paclitaxel in solid tumors, selected the recommended Phase 2 dose (RP2D), and initiated the Part II dose expansion portion of the trial. The company expects to report interim safety, efficacy, and translational data from this trial in the first half of 2021. Completed the Part I dose escalation portion of ORIC-101 in combination with enzalutamide in metastatic prostate cancer, selected the RP2D, and initiated the Part II dose expansion portion of the trial. The company expects to report interim safety, efficacy, and translational data from this trial in the second half of 2021. Presented preclinical data at the 32nd EORTC-NCI-AACR Symposium 2020 that demonstrated ORIC-101 reversed GR-mediated resistance to an androgen receptor (AR) degrader. ORIC-533: CD73 Inhibitor ORIC-533 is a highly potent, orally bioavailable CD73 inhibitor and has demonstrated more potent adenosine inhibition in preclinical studies compared to an antibody approach and other small molecule CD73 inhibitors. Conducted a preclinical collaboration with an academic key opinion leader that generated compelling single agent activity in patient derived model systems in an undisclosed tumor type. The company plans to pursue a single agent clinical development path in this indication. ORIC-533 continues to progress in Investigational New Drug (IND) enabling studies and the company expects to file an IND with the Food and Drug Administration (FDA) in the first half of 2021. ORIC-944: PRC2 Inhibitor ORIC-944 is a potent and selective allosteric inhibitor of polycomb repressive complex 2 (PRC2) that targets its regulatory embryonic ectoderm development (EED) subunit and has demonstrated single agent efficacy in multiple enzalutamide-resistant prostate cancer models in preclinical studies. Licensed exclusive worldwide development and commercialization rights from Mirati Therapeutics, Inc. in August 2020. ORIC-944 continues to progress in IND enabling studies and the company expects to file an IND with the FDA in the second half of 2021, with initial clinical development as a single agent in treatment-resistant prostate cancer. ORIC-114: EGFR/HER2 Inhibitor ORIC-114 is a brain penetrant, orally bioavailable, irreversible inhibitor designed to selectively target EGFR and HER2 with high potency against exon 20 insertion mutations. Licensed exclusive development and commercialization rights worldwide excluding the People’s Republic of China, Hong Kong, Macau and Taiwan from Voronoi, Inc. in October 2020. ORIC-114 continues to progress in IND enabling studies and the company expects to file a Clinical Trial Application (CTA) in South Korea in the second half of 2021. Corporate: The company completed a public offering of common stock in November 2020, raising gross proceeds of $133.3 million. Anticipated Milestones ORIC anticipates the following milestones in 2021: ORIC-101: Report interim safety, efficacy, and translational data from ongoing combination trial with nab-paclitaxel in the first half of 2021 ORIC-101: Report interim safety, efficacy, and translational data from ongoing combination trial with enzalutamide in the second half of 2021 ORIC-533: File an IND in the first half of 2021 ORIC-944: File an IND in the second half of 2021 ORIC-114: File a CTA in the second half of 2021 Present additional preclinical and translational research data on ORIC-101, ORIC-533, ORIC-944, and ORIC-114 at scientific conferences in 2021 Fourth Quarter and Full year 2020 Financial Results Cash, Cash Equivalents and Short-term Investments: Cash, cash equivalents and short-term investments totaled $293.6 million as of December 31, 2020, which included gross proceeds of $133.3 million from the follow-on financing completed in November 2020. The company expects its current cash, cash equivalents and short-term investments will be sufficient to fund its current operating plan into the second half of 2023. Cash, cash equivalents and short-term investments totaled $293.6 million as of December 31, 2020, which included gross proceeds of $133.3 million from the follow-on financing completed in November 2020. The company expects its current cash, cash equivalents and short-term investments will be sufficient to fund its current operating plan into the second half of 2023. R&D Expenses: Research and development (R&D) expenses were $12.1 million for the three months ended December 31, 2020, compared to $7.0 million for the three months ended December 31, 2019, an increase of $5.1 million. For the year ended December 31, 2020, R&D expenses were $35.9 million compared to $22.8 million for the same period of 2019, an increase of $13.1 million. The increases for the 2020 periods were primarily driven by an increase in external expenses related to the advancement of ORIC-101, ORIC-533 and exploratory research programs, as well as higher personnel costs, including additional non-cash stock-based compensation of $0.4 million and $1.5 million for the three and twelve months ended December 31, 2020, as compared to the same periods in 2019, respectively. Research and development (R&D) expenses were $12.1 million for the three months ended December 31, 2020, compared to $7.0 million for the three months ended December 31, 2019, an increase of $5.1 million. For the year ended December 31, 2020, R&D expenses were $35.9 million compared to $22.8 million for the same period of 2019, an increase of $13.1 million. The increases for the 2020 periods were primarily driven by an increase in external expenses related to the advancement of ORIC-101, ORIC-533 and exploratory research programs, as well as higher personnel costs, including additional non-cash stock-based compensation of $0.4 million and $1.5 million for the three and twelve months ended December 31, 2020, as compared to the same periods in 2019, respectively. IPR&D Expenses: In-process research and development (IPR&D) expenses of $11.9 million and $24.8 million for the three and twelve months ended December 31, 2020 related to charges the company recorded for the cash payment and fair value of common stock shares issued to Mirati and Voronoi for the development and commercialization rights to ORIC-944 and ORIC-114. There were no similar costs incurred in 2019. In-process research and development (IPR&D) expenses of $11.9 million and $24.8 million for the three and twelve months ended December 31, 2020 related to charges the company recorded for the cash payment and fair value of common stock shares issued to Mirati and Voronoi for the development and commercialization rights to ORIC-944 and ORIC-114. There were no similar costs incurred in 2019. G&A Expenses: General and administrative (G&A) expenses were $4.3 million for the three months ended December 31, 2020, compared to $1.8 million for the three months ended December 31, 2019, an increase of $2.5 million. For the year ended December 31, 2020, G&A expenses were $13.4 million compared to $5.7 million for the same period in 2019, an increase of $7.7 million. These increases were primarily due to higher personnel costs, including additional non-cash stock-based compensation of $0.9 million and $2.7 million for the three and twelve months ended December 31, 2020, as compared to the same periods in 2019, respectively, higher professional services and related costs to operate as a public company. About ORIC Pharmaceuticals, Inc. ORIC Pharmaceuticals is a clinical stage biopharmaceutical company dedicated to improving patients’ lives by O vercoming R esistance I n C ancer. ORIC’s lead product candidate, ORIC-101, is a potent and selective small molecule antagonist of the glucocorticoid receptor, which has been linked to resistance to multiple classes of cancer therapeutics across a variety of solid tumors. ORIC-101 is currently in two separate Phase 1b trials in combination with (1) Abraxane (nab-paclitaxel) in advanced or metastatic solid tumors and (2) Xtandi (enzalutamide) in metastatic prostate cancer. ORIC’s other product candidates include (1) ORIC-533, an orally bioavailable small molecule inhibitor of CD73, a key node in the adenosine pathway believed to play a central role in resistance to chemotherapy- and immunotherapy-based treatment regimens, (2) ORIC-944, an allosteric inhibitor of the polycomb repressive complex 2 (PRC2) via the EED subunit, being developed for prostate cancer, and (3) ORIC-114, a brain penetrant inhibitor designed to selectively target EGFR and HER2 with high potency against exon 20 insertion mutations, being developed across multiple genetically defined cancers. Beyond these four product candidates, ORIC is also developing multiple precision medicines targeting other hallmark cancer resistance mechanisms. ORIC has offices in South San Francisco and San Diego, California. For more information, please go to , and follow us on Twitter or LinkedIn. Cautionary Note Regarding Forward-Looking Statements This press release contains forward-looking statements as that term is defined in Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. Statements in this press release that are not purely historical are forward-looking statements. Such forward-looking statements include, among other things, statements regarding ORIC’s development plans and timelines; the potential advantages of ORIC’s product candidates and programs; plans underlying ORIC-101 clinical trials and development; the expected timing of reporting interim data from the ORIC-101 clinical trials; plans underlying ORIC-533, ORIC-944, ORIC-114 or any other programs; the planned IND filings for ORIC-533 and ORIC-944 and CTA filing for ORIC-114; ORIC’s anticipated 2021 milestones; the period over which ORIC estimates its existing cash, cash equivalents and short-term investments will be sufficient to fund its current operating plan; and statements by the company’s president and chief executive officer. Words such as “believes,” “anticipates,” “plans,” “expects,” “intends,” “will,” “goal,” “potential” and similar expressions are intended to identify forward-looking statements. The forward-looking statements contained herein are based upon ORIC’s current expectations and involve assumptions that may never materialize or may prove to be incorrect. Actual results could differ materially from those projected in any forward-looking statements due to numerous risks and uncertainties, including but not limited to: risks associated with the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics and operating as an early clinical stage company; ORIC’s ability to develop, initiate or complete preclinical studies and clinical trials for, obtain approvals for and commercialize any of its product candidates; changes in ORIC’s plans to develop and commercialize its product candidates; the potential for clinical trials of ORIC-101, ORIC-533, ORIC-944, ORIC-114 or any other product candidates to differ from preclinical, interim, preliminary or expected results; negative impacts of the COVID-19 pandemic on ORIC’s operations, including clinical trials; the risk of the occurrence of any event, change or other circumstance that could give rise to the termination of ORIC’s license agreements; ORIC’s ability to raise any additional funding it will need to continue to pursue its business and product development plans; regulatory developments in the United States and foreign countries; ORIC’s reliance on third parties, including contract manufacturers and contract research organizations; ORIC’s ability to obtain and maintain intellectual property protection for its product candidates; the loss of key scientific or management personnel; competition in the industry in which ORIC operates; general economic and market conditions; and other risks. Information regarding the foregoing and additional risks may be found in the section entitled “Risk Factors” in ORIC’s Quarterly Report on Form 10-K filed with the Securities and Exchange Commission (the “SEC”) on March 23, 2021, and ORIC’s future reports to be filed with the SEC. These forward-looking statements are made as of the date of this press release, and ORIC assumes no obligation to update the forward-looking statements, or to update the reasons why actual results could differ from those projected in the forward-looking statements, except as required by law. Contact: Dominic Piscitelli, Chief Financial Officer dominic.piscitelli@oricpharma.com info@oricpharma.com ORIC PHARMACEUTICALS, INC. CONDENSED BALANCE SHEETS (in thousands, except share and per share amounts) ORIC PHARMACEUTICALS, INC. STATEMENTS OF OPERATIONS AND COMPREHENSIVE LOSS (Unaudited) (in thousands, except share and per share amounts)