3β-HSD1

In collaboration with leading cancer centers, research results to be presented from eight studies across four tumor types, demonstrating Caris' impact on precision medicine IRVING, Texas, Jan. 23, 2024 /PRNewswire/ -- Caris Life Sciences®(Caris), the leading next-generation AI TechBio company and precision medicine pioneer that is actively developing and delivering innovative solutions to revolutionize healthcare and improve the human condition using molecular science and AI, today announced that the company and collaborators within the Caris Precision Oncology Alliance™ (POA) will collectively present eight studies across four tumor types at the 2024 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, January 25-27, 2024 in San Francisco. The findings demonstrate the continued and expanded capabilities of Caris' comprehensive multi-modal database to enable novel insights into cancer that could have profound effects on a patient's diagnosis, prognosis, care plan and response to treatment. Continue Reading "These presentations illustrate how our physicians, scientists and collaborators in the POA are leveraging real-world clinical evidence from over 593,000 lifetime clinical cases, including over 482,000 with matched molecular data and outcomes, in Caris' unique AI-driven platform to deepen our understanding of cancer and to develop the next breakthrough medicines," said Chadi Nabhan, MD, MBA, FACP, Chairman of the Caris Precision Oncology Alliance. "Caris molecular profiling enables deep exploration of the genetic and immune landscapes of cancer, providing insights into which signaling pathways explain the pathobiology of disease and leading to more precise targeted therapy. That's a major focus of the wide array of research Caris and our POA collaborators will proudly present at this year's ASCO GU." The findings demonstrate the continued and expanded capabilities of Caris' comprehensive multi-modal database Post this Oral Abstract: A Caris study entitled "Differences in genomic, transcriptomic, and immune landscape of prostate cancer (PCa) based on site of metastasis (mets)" will be presented by Dr. Umang Swami from the Huntsman Cancer Institute on Thursday, January 25 at 4:20 p.m. PST during Rapid Oral Abstract Session A on Prostate Cancer in the Level 3 Ballroom. The research is a collaboration with the Huntsman Cancer Institute at the University of Utah and other POA members. Compared to primary PCa, both visceral (liver and lung) and non-visceral (lymph node and bone) metastases had higher Androgen Receptor (AR) and interferon g signaling, upregulation of the E2F, G2M checkpoints and MYC target pathways, and were significantly less enriched in macrophage M2, NK, and regulatory T cells. Visceral metastases also had higher neuroendocrine (NEPC) scores and were less enriched for B cells and neutrophils. These data on the molecular and immunologic mechanisms of metastatic tropism in advanced PCa may facilitate future drug development. Additional Presentations Reveal Potential Impact of Comprehensive Molecular Profiling Caris will present additional data from studies demonstrating the critical role of comprehensive molecular profiling in the treatment of genitourinary cancers. Poster and abstract summaries highlighting this research will be available onsite at Caris' booth (#8). The full abstracts will be available through Caris' website beginning on January 23. Survival outcomes in patients (pts) with prostatic cancer (PCa) based on pathologically confirmed sites of metastasis (January 25; Poster C7, Abstract 72) Examination of 6,069 PCa specimens in Caris' CODEai multi-modal database showed that metastasis to the liver was associated with overall survival significantly shorter than metastasis to the lung, arguing against combining them into the single category of visceral metastases as a stratification factor in randomized clinical trials. Correlation of PIM kinases with tumor immune microenvironment and clinical presentation of metastatic hormone-sensitive prostate cancer January 25; Poster J19, Abstract 211) In a study of 44 patients with treatment-naive metastatic hormone-sensitive prostate cancer (mHSPC), there was a strong association of high expression of PIM kinases with increased MAPK activation score, T cell inflamed score, inflammatory, PSA, AR, MHC class I and MHC class II gene expression, and differential immune cell infiltration. However, this did not significantly translate to a worse clinical presentation of mHSPC. A better understanding of these differences with additional research may provide a rationale for tailored therapeutic approaches for PIM-expressing mHSPC. The influence of the germline HSD3B1 adrenal-permissive variant (c.1100 C) on somatic alteration landscape, transcriptome, and immune-cell infiltration in prostate cancer ( January 25; Poster K3, Abstract 215) In a study of 5,421 prostate cancer biopsies from the Caris Life Sciences database, the homozygous adrenal-permissive HSD3B1 variant (c.1100 CC) was characterized by elevated AR signaling and MAPK activation and a unique immune-cell regulatory landscape, with higher B7-H3 expression, increased intratumoral dendritic cells and decreased immunosuppressive neutrophils, suggesting that B7-H3–targeted therapies might be effective against this class of cancer. The opposing effects of Class 1B and Class 2 FOXA1 mutations in prostate cancer (January 25; Poster K4, Abstract 216) Alterations in the FOXA1 transcription factor are present in 16% of prostate cancers (PCa), but different alterations exhibit divergent molecular and clinical profiles. In a study of more than 4,000 primary and metastatic PCa samples, missense mutations in the Wing2 region of FOXA1 (a.a. 248-269) had better response to androgen deprivation therapy (ADT), whereas mutations in a.a. R219, a highly conserved DNA contact residue, were associated with a neuroendocrine phenotype and showed poor survival with ADT. Canonical Wnt signaling pathway (WSP) alterations in metastatic prostate cancer (January 25; Poster K9, Abstract 221) In a study of 4,150 total PCa samples, 722 with aberrant canonical Wnt signaling (WSP-act), WSP-act tumors had pronounced upregulation of ROR1 gene expression and augmented levels of M2 macrophages, suggesting that ROR1 may contribute to immune evasion in WSP-act mPCa. Comprehensive analysis of targetable alterations in urachal cancer by NGS ( January 26; Poster K7, Abstract 663) In a comprehensive characterization the molecular and immune landscape of urachal cancer (UrC), UrC tumors rarely harbored predictive markers of response to immunotherapy, suggesting limited efficacy in this patient population. However, the recurrence of MAPK alterations and associated pathway activation in UrC warrants further investigation of MAPK-targeted therapies in prospective clinical trials. IL-6 and PIM1 expression in renal cell carcinoma ( January 27; Poster K11, Abstract 470) Based on the hypothesis that an IL-6/JAK/STAT pathway regulates the expression of PIM1 in renal cell carcinoma (RCC) as in pancreatic and breast cancer, the transcriptomes of RCC samples in the Caris multi-modal database were analyzed, showing that PIM1 expression was significantly increased in metastatic relative to primary RCC. IL-6 expression was up to 6.5-fold higher in RCC patients with PIM1 overexpression. Outcomes data showed that PIM1 overexpression was associated with decreased overall survival for RCC patients independent of treatment received. Since multiple FDA-approved agents are available that target this pathway, further investigation is warranted to determine the efficacy of these agents in pre-clinical models and clinical trials of RCC. The POA includes 90 cancer centers, academic institutions, research consortia and healthcare systems, including 42 NCI-designated cancer centers, collaborating to advance precision oncology and biomarker-driven research. POA members work together to establish and optimize standards of care for molecular testing through innovative research focused on predictive and prognostic markers that improve the clinical outcomes for cancer patients. About Caris Life Sciences Caris Life Sciences® (Caris) is the leading next-generation AI TechBio company and precision medicine pioneer that is actively developing and delivering innovative solutions to revolutionize healthcare and improve the human condition using molecular science and AI. Through comprehensive molecular profiling (Whole Exome and Whole Transcriptome Sequencing) and the application of advanced AI and machine learning algorithms, Caris has created the large-scale, multi-modal database and computing capability needed to analyze and unravel the molecular complexity of disease. This convergence of sequencing power, big data and AI technologies provides an unmatched platform to deliver the next-generation of precision medicine tools for early detection, diagnosis, monitoring, therapy selection and drug development. Headquartered in Irving, Texas, Caris has offices in Phoenix, New York, Cambridge (MA), Tokyo, Japan and Basel, Switzerland. Caris or its distributor partners provide services in the U.S., Europe, Asia and other international markets. To learn more, please visit CarisLifeSciences.com. Caris Life Sciences Media Contact: Lisa Burgner [email protected] 214.294.5606 SOURCE Caris Life Sciences

The HSD3B1 gene could hold clues for predicting and treating endometrial cancer, according to a novel finding. Researchers found a certain HSD3B1 genotype was more common in women with type 2 endometrial cancer. Those patients show lower survival rates than those diagnosed with type 1 endometrial cancer, likely driven by the fact that type 2 patient cells are less hormone-dependent. The HSD3B1 gene could hold clues for predicting and treating endometrial cancer, according to a novel finding from the Cleveland Clinic's Lerner Research Institute. Researchers found a certain HSD3B1 genotype was more common in women with type 2 endometrial cancer, according to the results published in JNCI Cancer Spectrum. Those patients show lower survival rates than those diagnosed with type 1 endometrial cancer, likely driven by the fact that type 2 patient cells are less hormone-dependent. The results are the latest step in untangling the role HSD3B1's genotype plays in hormone-driven cancers, with previous research revealing associations with breast and prostate cancer. This body of work was in part led by Cleveland Clinic researchers and physician-scientists, and continues today with translational research and clinical trials. HSD3B1 researchers are building a foundation for future options to treat and prevent cancer subtypes with a lower survival rate, says Nima Sharifi, MD, senior author of the paper and Director of the Lerner Research Institute's Genitourinary Malignancies Research Center. Despite being one of the most common cancers among women, there is no test or exam to screen for endometrial cancer. Incidence rates for this "underfunded and understudied" disease are rising in the United States, says Roberto Vargas, MD, co-author and assistant staff at the Cleveland Clinic's Division of Gynecologic Oncology. "Over the past three decades, we haven't moved the bar on outcomes," Dr. Vargas says. "Figuring out the interplay between this gene and endometrial cancer can pave a way to screen and treat it more effectively." HSD3B1 is a gene that regulates androgens and estrogens by producing the enzyme that converts adrenal steroid-precursors to androgens and estrogens. HSD3B1's genotype is either adrenal-permissive, which amplifies the process, or adrenal-restrictive, which limits it. Dr. Sharifi likens HSD3B1's role in the adrenal pathway to how a dam controls water. Opening the gates releases a rush of water, but when the dam is closed, that flow is held back. Previous research established how HSD3B1 genetics works and associates with hormone-associated cancers, starting with castration-resistant prostate cancer. When a patient undergoes chemical or surgical castration to treat prostate cancer, the procedure halts one of the body's paths to producing androgens. When the body stops producing androgens or estrogens through sex organs, the body can still produce these hormones through the adrenal pathway, Dr. Sharifi says. Castration is intended to stop androgen production when tumors grow in response to the hormone. When the adrenal pathway starts producing androgens, that can lead to recurrence. Previous research associates adrenal-permissive HSD3B1 with poorer outcomes in castration-resistant prostate cancer across multiple cohorts. Dr. Sharifi says HSD3B1 could serve as a biomarker for breast and endometrial cancer subtypes because the ovaries stop producing estrogen after menopause. The adrenal pathway could then kick in to start producing those hormones. The median endometrial cancer patient age is 60 years old, with the main symptom being irregular bleeding after menopause. Recent research investigated potential association between HSD3B1's genotype and postmenopausal breast and endometrial cancer subtypes, where the cancer grows in response to estrogen. Previous research associated ER+ cancer in postmenopausal women with HSD3B1 adrenal-permissive genotype. Dr. Sharifi's research team, through analyzing TCGA data, added to this finding by showing an association between the opposite HSD3B1 genotype, adrenal-restrictive, and a certain subtype of ER- breast cancer. In endometrial cancer, the serous subtype has less ER expression and is associated with a worse prognosis. The adrenal-restrictive HSD3B1 genotype was more commonly associated with serous-type endometrial cancer, according to the study. Additionally, in an analysis of UK Biobank data, adrenal-restrictive genotype was shown to be associated with worse outcomes among endometrial cancer patients. Jeff McManus, PhD, first author and a research associate in the Cancer Biology Department, says researchers will now need to validate the results with much larger cohorts. That will include examining HSD3B1 associations with survival rates within different cancer subtypes. Ongoing HSD3B1 collaborations include further research on HSD3B1's relationship with breast and endometrial cancer, as well as investigation into how HSD3B1 is associated with response to radiotherapy. Clinical trials for prostate cancer held at the Cleveland Clinic will test how people with specific HSD3B1 genotypes respond to therapeutics. Authors noted that Black women are more likely inherit adrenal-restrictive HSD3B1 and that certain breast and endometrial cancer subtypes that have worse outcomes -- and both are more common in Black women. Black women also were twice as likely to die from uterine cancer compared to other ethnic groups in a study released in May from the National Cancer Institute. "Chipping away at this difference in outcomes and trying to understand a genetic basis will be crucial in reducing (or eliminating) existing disparities," Vargas says.