WNT5A

Investigators have provided new understanding of how diabetes delays wound healing in the eye, identifying for the first time two related disease-associated changes to the cornea. Investigators from Cedars-Sinai have provided new understanding of how diabetes delays wound healing in the eye, identifying for the first time two related disease-associated changes to the cornea. The findings, published today in the peer-reviewed journal Diabetologia, also identified three therapeutic pathways that reversed these changes and partially restored wound-healing function to the cornea -- a discovery that could ultimately inform new treatments for diabetes. "We have found that diabetes induces more cellular changes than we were aware of previously," said Alexander Ljubimov, PhD, director of the Eye Program at Cedars-Sinai's Board of Governors Regenerative Medicine Institute and senior author of the paper. "The discovery does not affect gene sequence but entails specific DNA modifications altering gene expression -- what are known as epigenetic alterations." More than 37 million people in the United States -- 11% of the population -- have diabetes, a systemic disorder that can result in kidney disease, heart disease, amputation, stroke and nerve damage. Most diabetes drugs are designed to increase glucose tolerance or supply depleted insulin, but do not address molecular and cellular changes or their associated complications. The new research also identifies for the first time an important role of Wnt-5a, a secreted signaling protein investigators found responsible for corneal wound healing and the function of stem cells -- cells capable of differentiating into many cell types. "Current treatments only address symptoms, so there is an urgent need to understand the molecular mechanisms of diabetes-related wound-healing problems," said Ruchi Shah, PhD, a scientist in Ljubimov's lab and the study's first author. "Understanding of this novel epigenetically regulated wound-healing mechanism could lead to therapeutic treatments that could help patients avoid further long-term ocular health issues." Though much focus of diabetic eye disease is on the retina, up to 70% of diabetes patients suffer from problems of the cornea, the transparent, protective exterior surface of the eye. In advanced diabetes, corneal stem cells become dysfunctional, and the cornea heals more slowly and less completely following an injury or procedures such as cataract surgery and laser treatment for diabetic retinopathy. To identify the epigenetic changes discovered in this study -- changes not hard-wired into the genome from birth, but introduced later -- Ljubimov and his team compared cells from the corneas from six diabetic patients with those of five healthy donors. They found that in diabetic corneas, the protein product of the WNT5A gene was repressed. Additionally, in diabetic samples, they found an increase in the microRNA that inhibits WNT5A. The team of scientists then induced wounds to corneal cells in culture and corneal organ cultures, and tested three interventions designed to normalize Wnt-5a protein expression. They added the Wnt-5a protein directly; they introduced a DNA methylation inhibitor, originally approved to treat cancer; and they targeted microRNA levels with a novel gene therapy approach using a nanoscale compound. The team developed the compound, which uses synthetic molecules to block the microRNA, as a substitute for a viral gene therapy they found to be toxic to stem cells. All three therapeutic methods, in the diabetic samples, stimulated stem cell marker production and improved tissue regeneration, accelerating wound healing. "Novel therapies to reverse epigenetic effects could improve corneal function, and may also prove significant in other diabetic complications," said Clive Svendsen, PhD, director of the Board of Governors Regenerative Medicine Institute and study co-author. "This work certainly helps move the field forward." Investigators will continue to analyze their data to better understand the mechanisms of WNT5A and other genes related to wound healing. They are also studying a combination therapy to target both microRNA and DNA methylation in hopes that it will more thoroughly normalize wound healing by increasing Wnt-5a protein. "Our goal is to develop topical, sustained-release drugs for corneal wound healing," said Ljubimov. "Drugs that are FDA [Food and Drug Administration] approved and could be easily applied may be one of the most promising approaches for effective future therapies." Funding: This work was funded by National Institutes of Health grant numbers R01EY013431482, R01EY031377, R01EY025377, and R01CA206220; and the Cedars-Sinai Board of Governors Regenerative Medicine Institute.

Research results from five studies across three solid tumor types demonstrate the impact of Caris' approach to molecular profiling across the continuum of cancer care IRVING, Texas, Feb. 13, 2023 /PRNewswire/ -- Caris Life Sciences®(Caris), the leading molecular science and technology company actively developing and delivering innovative solutions to revolutionize healthcare, today announced that the company and partners within the Caris Precision Oncology Alliance™ (POA) will collectively present five studies across three tumor types at the 2023 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, February 16-18, 2023 in San Francisco (Tabletop #50). "We are proud of the growing number of collaborative abstracts accepted for presentation at ASCO GU, demonstrating the power of Caris' comprehensive molecular profiling and the large-scale collaboration between POA sites," said Chadi Nabhan, M.D., MBA, FACP, Chairman of the Caris Precision Oncology Alliance. "The findings represent important observations in prostate, urothelial, and renal cancers, which could lead to novel treatment strategies and knowledge that improve patient outcomes." "At Caris, our goal is to enable clinicians to make the best treatment choices for their patients, researchers to discover new targets, and the biopharmaceutical industry to develop the next breakthrough medicines," said David Spetzler, M.S., Ph.D., MBA, President and Chief Scientific Officer of Caris. "These presentations show how our physicians, scientists and partners in the POA are leveraging real-world clinical evidence from over 455,000 lifetime cases in Caris' unique AI-driven platform to deepen our understanding of cancer. These foundational discoveries provide key insights into advanced cancer and support the development of precision oncology approaches in advanced genitourinary tumors to better serve cancer patients." Poster presentations include: Clinical and Molecular Features of ATM and BRCA2 Mutations in Metastatic Prostate Cancer. (Poster Number: J8) February 16, 11:30 AM – 1:00 PM PST The Genomic Landscape of Urothelial Carcinoma with High and Low ERBB2/HER2 Expression. (Poster Number: M18) February 17, 12:30 – 2:00 PM PST Characterization and Impact of Wnt5A Signaling on Outcomes of Urothelial Carcinoma. (Poster Number: N3) February 17, 12:30 – 2:00 PM PST Exploration of Immunosuppressive Features of the Tumor Microenvironment within Hepatic and Non-Hepatic Tumors of Urothelial Origin. (Poster Number: N5) February 17, 12:30 – 2:00 PM PST Characterization of FOLH1 Expression in Renal Cell Carcinoma (RCC). (Poster Number: K8) February 18, 7:00 – 8:00 AM PST Poster and abstract summaries highlighting this research will be available onsite at Caris' Tabletop #50. The full abstracts will be available through the official ASCO website February 13. The Caris Precision Oncology Alliance includes 77 cancer centers and academic institutions in the United States and beyond. These institutions have early access to the extensive database and artificial intelligence platform within Caris to establish evidence-based standards for cancer profiling and molecular testing in oncology. By leveraging the comprehensive genomic, transcriptomic and proteomic data available through Caris molecular profiling, Caris seeks to provide this network with the ability to prioritize therapeutic options and determine which clinical trial opportunities may benefit their patients. POA members are also able to integrate with a growing portfolio of biomarker directed trials sponsored by biopharma. Additionally, as a member of the POA, institutions have access to Caris CODEai™, the most comprehensive data solution in the industry with cancer treatment information and real-world clinical outcomes evidence for over 350,000 patients covering over 1 million data points per patient. About Caris Life Sciences Caris Life Sciences® (Caris) is the leading molecular science and technology company actively developing and delivering innovative solutions to revolutionize healthcare and improve patient outcomes. Through comprehensive molecular profiling (Whole Exome and Whole Transcriptome Sequencing) and the application of advanced artificial intelligence (AI) and machine learning algorithms, Caris has created the large-scale clinico-genomic database and cognitive computing needed to analyze and unravel the molecular complexity of disease. This information provides an unmatched resource and the ideal path forward to conduct the basic, fundamental research to accelerate discovery for detection, diagnosis, monitoring, therapy selection and drug development to improve the human condition. With a primary focus on cancer, Caris' suite of market-leading molecular profiling offerings assesses DNA, RNA and proteins to reveal a molecular blueprint that helps patients, physicians and researchers better detect, diagnose and treat patients. The company's latest advancement, Caris Assure™, is a blood-based, circulating nucleic acids sequencing (cNAS) assay that combines comprehensive molecular analysis (Whole Exome and Whole Transcriptome Sequencing from blood) and serial monitoring – making it the most powerful liquid biopsy assay ever developed. Headquartered in Irving, Texas, Caris has offices in Phoenix, New York, Tokyo, Japan and Basel, Switzerland. Caris provides services throughout the U.S., Europe, Asia and other international markets. To learn more, please visit CarisLifeSciences.com or follow us on LinkedIn. Caris Life Sciences Media Contact: Lisa Burgner [email protected] 214.294.5606 SOURCE Caris Life Sciences

Updated MCL and CLL data from the ongoing Phase 1/2 study of zilovertamab and ibrutinib are encouraging and continue to improve over prior reportingThe ORR of 89% and CR rate of 43% for patients with MCL treated with zilovertamab plus ibrutinib compare favorably to the historical ORR of 66% and CR rate of 20% for ibrutinib monotherapy Median PFS and OS have not been reached after a median follow up of 19.5 months for patients with MCL treated with zilovertamab plus ibrutinib, which compares favorably to the historical median PFS and OS of 12.8 months and 25 months, respectively, for ibrutinib monotherapy Landmark PFS was 100% at 42 months for patients with CLL expressing p53 mutation/del(17p) treated with zilovertamab plus ibrutinib SAN DIEGO, Dec. 10, 2022 (GLOBE NEWSWIRE) -- Oncternal Therapeutics, Inc. (Nasdaq: ONCT), a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies, today announced updated interim clinical data from ongoing Phase 1/2 Study CIRM-0001 in an oral presentation at the American Society of Hematology (ASH) 2022 Annual Meeting. In the study, zilovertamab, an investigational anti-ROR1 monoclonal antibody, is being evaluated in combination with ibrutinib in patients with mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL) and in a recently opened cohort for patients with marginal zone lymphoma (MZL). The clinical trial is being conducted in collaboration with the University of California San Diego (UC San Diego) and has been partially funded by the California Institute for Regenerative Medicine (CIRM). “The data presented in today’s oral session further strengthens our confidence in the significant clinical benefit the combination of zilovertamab and ibrutinib can provide to patients with MCL and CLL. The rapid onset of deep responses in patients with MCL supports our recently initiated randomized global registrational Phase 3 Study ZILO-301 of the combination of zilovertamab plus ibrutinib,” said James Breitmeyer, M.D., Ph.D., Oncternal’s President and CEO. “The robust response rates and prolonged PFS seen for MCL and CLL patients expressing the p53 mutation/del(17p), who are underserved by current standard of care treatments, is especially exciting. We continue to believe that the inhibition of ROR1 with zilovertamab can play a key role in addressing important unmet medical needs in difficult-to-treat patients across various hematological malignancies.” The updated interim data presented during an oral presentation at the ASH 2022 meeting include 33 patients with relapsed/refractory (R/R) MCL enrolled in the dose-finding and dose-expansion cohorts of Study CIRM-0001 (Part 1 + Part 2), of whom 28 were evaluable for efficacy as of the October 11, 2022 data cut-off date. Patients had high-risk factors and were heavily pre-treated at study entry, with 52% having a high Ki-67 proliferative index (≥30%), 47% with p53 mutations or deletions in chromosome 17p (del(17p)), and 46% having an intermediate or high sMIPI prognostic score.The objective response rate (ORR) was 89% (25 of 28 evaluable patients) and includes recently enrolled patients.The complete response (CR) rate was 43% (12 of 28 evaluable patients) at 26 months and was already 18% (5 of 28 evaluable patients) at 3 months.Historical data published for single agent ibrutinib for 370 patients with R/R MCL from three clinical trials showed an ORR of 66%, CR rate of 20% and median PFS of 12.8 months (Rule 2017, British Journal of Haematology).The partial response (PR) rate was 46% (13 of 28 evaluable patients), and the stable disease (SD) rate was 4% (1 of 28 evaluable patients), for a total clinical benefit rate (CR, PR and SD) of 93%.The median PFS has not been reached after a median follow-up of 19.5 months (95% CI: 19.4, 28.5), regardless of the number of prior systemic therapies.Median PFS was also favorable in patients with high-risk features associated with disease difficult-to-treat with BTK inhibitors: P53 mutation/del(17p): median PFS not reached (95% CI: 2.85, NE). Historical data for single agent ibrutinib in 20 patients with p53 mutation showed a median PFS of 4.0 months (Rule 2019, Haematologica).Ki-67 ≥30%: median PFS 33.2 months (95% CI: 2.85, NE).>1 prior systemic therapy: median PFS not reached (95% CI: 4.33, NE). Thirty-four patients with CLL in the dose-finding and dose-confirming cohorts of this clinical trial (Part 1 & Part 2) as of the October 11, 2022 data cut-off date were all evaluable for efficacy. Patients had high-risk factors, and most were heavily pre-treated at study entry, with a median of two systemic prior therapies (range 1-9). Landmark PFS was 100% at 42 months in patients with R/R CLL expressing p53 mutation/del(17p) treated with the combination of zilovertamab plus ibrutinib. The most recent data update from the ALPINE study in patients with R/R CLL expressing p53 mutation/del(17p) showed a landmark PFS of 77.6% at 24 months for zanubrutinib monotherapy and 55.7% at 24 months for ibrutinib monotherapy (Brown 2022, ASH).Landmark PFS was 95% at 24 months in all patients with R/R CLL treated with the combination of zilovertamab plus ibrutinib. The most recent data update from the ALPINE study in R/R CLL patients showed a landmark PFS at 24 months of 79.5% for zanubrutinib and 67.3% for ibrutinib monotherapy (Brown 2022, ASH).The median overall survival (OS) was not reached at 40 months for patients with CLL with p53 mutation/del(17p). Thirty-one patients with CLL have also been enrolled in the randomized efficacy cohort of this clinical trial (Part 3), of which 23 were evaluable for efficacy. Data from this cohort are maturing. The median PFS had not been reached for either group as of the October 11, 2022 cut-off date after a median follow up of 29 months. The combination of zilovertamab plus ibrutinib has been well tolerated as of the October 11, 2022 cut-off date, with treatment emergent adverse events consistent with or slightly improved compared to those reported for ibrutinib alone. There have been no dose-limiting toxicities and no serious adverse events attributed to zilovertamab alone. Atrial fibrillation was observed in only 9.4% of the patients and febrile neutropenia in 1.2% of patients. About the CIRM-0001 StudyThe CIRM-0001 Study is a Phase 1/2 trial evaluating zilovertamab in combination with ibrutinib in separate groups of patients with CLL, MCL or MZL. Enrollment of the dose-finding cohorts in CLL and MCL, dose-expansion cohort in CLL and MCL and randomized Phase 2 cohort in CLL has been completed. An additional dose-expansion cohort of up to 10 patients with MZL has started enrolling patients. Additional information about the CIRM-0001 clinical trial and other clinical trials of zilovertamab may be accessed at ClinicalTrials.gov. About ZilovertamabZilovertamab is an investigational, humanized, potentially first-in-class monoclonal antibody targeting Receptor tyrosine kinase-like Orphan Receptor 1 (ROR1). A Phase 3 registrational trial evaluating zilovertamab plus ibrutinib versus ibrutinib plus placebo in relapsed or refractory Mantle Cell Lymphoma (MCL) has been initiated (NCT05431179). Zilovertamab is also being studied in a Phase 1/2 clinical trial in combination with ibrutinib for the treatment of patients with MCL, chronic lymphocytic leukemia (CLL) or marginal zone lymphoma (MZL), in a collaboration with the University of California San Diego (UC San Diego) School of Medicine and the California Institute for Regenerative Medicine (CIRM). In addition, Oncternal is supporting two investigator-sponsored studies being conducted at the UC San Diego School of Medicine, a Phase 1b clinical trial for patients with metastatic castration-resistant prostate cancer (mCRPC), and a Phase 2 clinical trial of zilovertamab in combination with venetoclax, a Bcl-2 inhibitor, for patients with relapsed/refractory CLL. Both are open for enrollment. ROR1 is a potentially attractive target for cancer therapy because it is an onco-embryonic antigen, not usually expressed on adult cells, but its expression confers a survival and fitness advantage when reactivated and expressed by tumor cells. Researchers at the UC San Diego School of Medicine discovered that targeting a critical epitope on ROR1 was key to specifically inhibiting ROR1-expressing tumors. This led to the development of zilovertamab which binds this critical epitope of ROR1, highly expressed on many different cancers but not on normal tissues. Preclinical data showed that when zilovertamab bound to ROR1, it blocked Wnt5a signaling, inhibited tumor cell proliferation, migration and survival, and induced differentiation of the tumor cells. The FDA has granted Orphan Drug Designations to zilovertamab for the treatment of patients with MCL and CLL/small lymphocytic lymphoma. Zilovertamab is in clinical development and has not been approved by the FDA for any indication. About Oncternal TherapeuticsOncternal Therapeutics is a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies for the treatment of patients with cancers that have critical unmet medical need. Oncternal pursues drug development targeting promising, yet untapped biological pathways implicated in cancer generation or progression, focusing on hematological malignancies and prostate cancer. The lead clinical program is zilovertamab, an investigational monoclonal antibody designed to inhibit the function of Receptor Tyrosine Kinase-Like Orphan Receptor 1 (ROR1). ZILO-301, a global Phase 3 Study to evaluate zilovertamab in combination with ibrutinib for the treatment of patients with relapsed/refractory mantle cell lymphoma (MCL) has been initiated (NCT05431179). Zilovertamab continues to be evaluated in an ongoing Phase 1/2 study in combination with ibrutinib for the treatment of patients with MCL and chronic lymphocytic leukemia (CLL), and this trial was recently amended to include patients with marginal zone lymphoma (MZL) (NCT03088878). Zilovertamab is also being evaluated in two investigator-initiated studies, including a Phase 2 clinical trial of zilovertamab in combination with venetoclax, a Bcl-2 inhibitor, in patients with relapsed/refractory CLL, and in a Phase 1b study of zilovertamab in combination with docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC). Oncternal is also moving into the clinic with ONCT-808, an autologous chimeric antigen receptor T (CAR T) cell therapy that targets ROR1, with an active U.S. IND as of the end of September 2022 for the treatment of patients with relapsed or refractory aggressive B-cell lymphoma, including patients who have failed previous CD19 CAR T treatment. The preclinical pipeline also includes ONCT-534, a dual-action androgen receptor inhibitor (DAARI) that is undergoing final IND-enabling studies, as a potential treatment for castration resistant prostate cancer, including those with unmet medical need due to resistance to approved, standard of care androgen receptor inhibitors. More information is available at https://oncternal.com/. Forward-Looking InformationOncternal cautions you that statements included in this press release that are not a description of historical facts are forward-looking statements. In some cases, you can identify forward-looking statements by terms such as “may,” “will,” “should,” “expect,” “plan,” “anticipate,” “could,” “intend,” “target,” “project,” “contemplates,” “believes,” “estimates,” “predicts,” “potential” or “continue” or the negatives of these terms or other similar expressions. These statements are based on Oncternal’s current beliefs and expectations. Forward-looking statements include statements regarding the potential for zilovertamab in combination with ibrutinib to treat MCL, CLL or MZL; and the potential that Study ZILO-301 can serve as a registrational clinical trial. Forward-looking statements are subject to risks and uncertainties inherent in Oncternal’s business, including risks associated with the clinical development and process for obtaining regulatory approval of Oncternal’s product candidates, such as potential delays in the commencement, enrollment and completion of clinical trials; we have not conducted head-to-head studies of zilovertamab in combination with ibrutinib compared to ibrutinib monotherapy and data from separate studies may not be directly comparable due to the differences in study protocols, conditions and patient populations; the risk that interim results of a clinical trial do not predict final results and that one or more of the clinical outcomes may materially change as patient enrollment continues, following more comprehensive reviews of the data, as follow-up on the outcome of any particular patient continues, and as more patient data become available; later developments with the FDA may be inconsistent with the minutes from the completed end of Phase 2 meeting, including that the proposed Study ZILO-301 that may not support registration of zilovertamab in combination with ibrutinib which is a review issue with the FDA upon submission of a BLA; and other risks described in Oncternal’s filings with the U.S. Securities and Exchange Commission. All forward-looking statements in this press release are current only as of the date hereof and, except as required by applicable law, Oncternal undertakes no obligation to revise or update any forward-looking statement, or to make any other forward-looking statements, whether as a result of new information, future events or otherwise. All forward-looking statements are qualified in their entirety by this cautionary statement. This caution is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Contact Information: InvestorsRichard Vincent858-434-1113rvincent@oncternal.com MediaCorey Davis, Ph.D.LifeSci Advisors212-915-2577cdavis@lifesciadvisors.com