PIM1

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

– DSP-5336, an Investigational Menin and Mixed-lineage Leukemia Inhibitor, is Being Evaluated in Patients with Relapsed or Refractory Acute Leukemia, with Positive Preliminary Data Presented at ASH – CAMBRIDGE, Mass., Dec. 11, 2023 /PRNewswire/ -- Sumitomo Pharma America, Inc. (SMPA) today announced new data from the ongoing Phase 1/2 first-in-human study of DSP-5336, in patients with relapsed or refractory acute leukemia, presented at the 65th American Society of Hematology (ASH) Annual Meeting & Exposition. DSP-5336 is an investigational small molecule inhibitor of the menin and mixed-lineage leukemia (MLL) protein interaction, which plays key roles in biological pathways, including cell growth regulation, cell cycle control, genomic stability, bone development, and hematopoiesis.1,2,3 Data from the open-label, ongoing dose determination portion of the Phase 1/2 study enrolling patients with relapsed or refractory acute leukemia with relevant genomic alterations receiving oral DSP-5336 up to 200 mg twice-daily were presented at the meeting. In the ongoing study, patients are continuing to dose escalate and are now at therapeutic levels. Preliminary results presented at ASH 2023 included four evaluable patients treated with DSP-5336 200 mg twice-daily, three of whom showed objective responses. Clinical remission with partial hematologic recovery and clinical remission with incomplete count recovery (CRh/CRi) was achieved by one patient, CRi was achieved by one patient, and morphologic leukemia-free state (MLFS) was achieved by one patient. All patients cleared peripheral blasts. To date, DSP-5336 has been well-tolerated, notably, with no treatment-related cardiac effects, including QT prolongation. Additionally, differentiation syndrome has not been observed at the 200 mg twice-daily dose. "While these data are early-stage, it is encouraging to see promising clinical activity from DSP-5336, particularly with limited safety signals and a clean tolerability pro date," said Navel Daver, M.D., Director, Department of Leukemia, Division of Leukemia Research Alliance Program, The University of Texas MD Anderson Cancer Center and lead author on the DSP-5336 poster at ASH. "DSP-5336 is an investigational targeted therapy that inhibits menin-MLL protein interaction. Inhibition of the menin-MLL protein interaction may be able to reverse the leukemogenic activity of MLL fusion proteins and may be a future therapeutic option for acute leukemia." Leukemia is a type of cancer that forms in blood-forming tissue, characterized by the uncontrolled growth of blood cells, usually white blood cells in the bone marrow.4 Acute leukemia, a form of leukemia, requires immediate treatment as blood cells multiply rapidly leading to a sudden onset of symptoms.4 "There is a high unmet need for new and innovative approaches in the treatment of relapsed or refractory acute leukemia, as many patients have limited options to treat the disease or do not respond to currently available cancer therapies," said Jatin Shah, M.D., Chief Oncology Development Officer, SMPA. "We believe we are close to determining the appropriate therapeutic dose of DSP-5336 in our ongoing study and were encouraged by our discussions on these results with the leading hematological oncology community at ASH. We look forward to continuing the study of DSP-5336 as a monotherapy and to exploring additional combination studies." Additional SMPA data presented at ASH included an oral presentation of encouraging preliminary results from the ongoing Phase 1/2 study of TP-3654 monotherapy in patients with relapsed or refractory myelofibrosis who were previously treated with or ineligible for a JAK inhibitor. About DSP-5336 DSP-5336 is an investigational small molecule inhibitor of the menin and mixed-lineage leukemia (MLL) protein interaction. Menin is a scaffold nuclear protein that plays various key roles in biological pathways, including cell growth regulation, cell cycle control, genomic stability, bone development, and hematopoiesis.1,2 In preclinical studies, DSP-5336 has shown selective growth inhibition in human acute leukemia cell lines with KMT2A (MLL) rearrangements or NPM1 mutations.1,3 DSP-5336 showed induced reduction of gene expression of HOXA9 and MEIS1, which are highly expressing leukemia associate genes, and increased expression of differentiation marker gene CD11b in the human acute leukemia cell lines with MLL rearrangements.5,6 DSP-5336 also showed growth inhibition and changes of gene expression levels of HOXA9, MEIS1 and CD11b on human acute leukemia patient samples with MLL rearrangements or NPM1 mutations.5,6 The safety and efficacy of DSP-5336 is currently being clinically evaluated in a Phase 1/2 dose escalation/dose expansion study in patients with relapsed or refractory acute leukemia (NCT04988555). The FDA granted Orphan Drug Designation for DSP-5336 for the indication of acute myeloid leukemia in June 2022. About TP-3654 TP-3654 is an oral investigational inhibitor of PIM1 kinase, which has shown potential antitumor and antifibrotic activity through multiple pathways, including induction of apoptosis in preclinical models.7,8 TP-3654 was observed to inhibit proliferation and induce apoptosis in murine and human hematopoietic cells expressing the clinically relevant JAK2V617F mutation.7 TP-3654 alone and in combination with ruxolitinib showed white blood cell and neutrophil count normalization, and also reduced spleen size and bone marrow fibrosis in JAK2V617F and MPLW515L murine models of myelofibrosis.8 The safety and efficacy of TP-3654 is currently being clinically evaluated in a Phase 1/2 study in patients with intermediate and high-risk myelofibrosis (NCT04176198). The U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation for TP-3654 for the indication of myelofibrosis in May 2022. About Sumitomo Pharma Sumitomo Pharma Co., Ltd. is a global pharmaceutical company based in Japan with key operations in the U.S. (Sumitomo Pharma America, Inc.), Canada (Sumitomo Pharma Canada, Inc.) and Europe (Sumitomo Pharma Switzerland GmbH) focused on addressing patient needs in psychiatry & neurology, oncology, urology, women's health, rare disease, and cell & gene therapies. With several marketed products in the U.S., Canada, and Europe, a diverse pipeline of early- to late-stage assets, and in-house advanced technology capabilities, we aim to accelerate discovery, research, and development to bring novel therapies to patients sooner. For more information, please visit and LinkedIn to follow us. The Sumitomo Pharma icon is a trademark of Sumitomo Pharma Co., Ltd., used under license. SUMITOMO PHARMA is a trademark of Sumitomo Pharma Co., Ltd., used under license. SUMITOMO is a registered trademark of Sumitomo Chemical Co., Ltd., used under license. Sumitomo Pharma America, Inc. is a U.S. subsidiary of Sumitomo Pharma Co., Ltd. © 2023 Sumitomo Pharma America, Inc. All rights reserved. For a copy of this release, visit Sumitomo Pharma America's website at . References Cierpicki T, Grembecka J. Challenges and opportunities in targeting the menin-MLL Interaction. Future Med Chem. 2014; 6(4):447-462. doi:10.4155/fmc.13.214. Matkar S, Thiel A, Hua X. Menin: a scaffold protein that controls gene expression and cell signaling. Trends Biochem Sci. 2013; 38(8):394-402. doi:10.1016/j.tibs.2013.05.005. Kuhn MWM, Song E, Feng Z, et al. Targeting chromatin regulators inhibits leukemogenic gene expression in NPM1 mutant leukemia. Cancer Discov. 2016; 6(10):1166-1181. doi:10.1158/2159-8290.CD-16-0237. Chennamadhavuni A, Lyengar V, Mukkamalla SKR, et al. Leukemia. [Updated 2023 Jan 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: . Eguchi K, Shimizu T, Kato D, et al. Preclinical Evaluation of a Novel Orally Bioavailable Menin-MLL Interaction Inhibitor, DSP-5336, for the Treatment of Acute Leukemia Patients with MLL-Rearrangement or NPM1 Mutation. Blood (2021) 138 (Supplement 1): 3339. . Daver N, Zeidner JF, Yuda J, et al. 2911 Phase 1/2 First-in-Human Study of the Menin-MLL Inhibitor DSP-5336 in Patients with Relapsed or Refractory Acute Leukemia. American Society of Hematology 2023. Available at: Foulks JM, Carpenter KJ, Luo B, et al. A small-molecule inhibitor of PIM kinases as a potential treatment for urothelial carcinomas. Neoplasia. 2014;16(5):403-412. Dutta A., Nath D, Yang Y, et al. Genetic ablation of Pim1 or pharmacologic inhibition with TP-3654 ameliorates myelofibrosis in murine models. Leukemia. 2022; 36 (3): 746-759. doi: 10.1038/s41375-021-01464-2.

– ASH Preliminary Data Includes New Clinical Results in Relapsed or Refractory Myelofibrosis (TP-3654) and Relapsed or Refractory Acute Leukemia (DSP-5336) – CAMBRIDGE, Mass., Nov. 3, 2023 /PRNewswire/ -- Sumitomo Pharma America, Inc. (SMPA) today announced preliminary clinical data for investigational agents TP-3654, a selective oral PIM1 kinase inhibitor, and DSP-5336, an inhibitor of the menin and mixed-lineage leukemia (MLL) protein interaction. These data will be presented at the 65th American Society of Hematology (ASH) Annual Meeting & Exposition, held December 9-12 in San Diego, Calif. Preliminary results from the ongoing Phase 1/2 study of TP-3654 monotherapy in patients with relapsed or refractory myelofibrosis who were previously treated with or ineligible for a JAK inhibitor will be presented in an oral presentation at ASH. In this study, oral TP-3654 was well-tolerated with limited myelosuppressive adverse events. TP-3654 exhibited early signs of clinical activity including spleen volume reduction, total symptom score improvement, and correlating cytokine reductions. SMPA will also present a poster on preliminary clinical data from the ongoing Phase 1/2 first-in-human study of oral DSP-5336, in patients with relapsed or refractory acute leukemia. Preliminary data showed that DSP-5336 was well-tolerated with no dose limiting toxicities, including no observed cardiac signals. Target pharmacodynamic changes were observed with treatment, including rapid decreases in genes commonly expressed in leukemia (HOXA9, MEIS1, and PBX3). These changes were seen particularly in patients with acute myeloid leukemia characterized by a KMT2A (MLL) gene rearrangement or a mutation in the NPM1 gene. "We are encouraged by the early signs of clinical activity shown in the preliminary results from the TP-3654 and DSP-5336 Phase 1/2 trials. We look forward to sharing the data and having important scientific engagement involving both agents at the annual ASH meeting in December," said Jatin Shah, M.D., Chief Oncology Development Officer, SMPA. "Improving patient outcomes and developing new oncological treatments is a primary focus for SMPA and we remain committed to exploring the potential of our diverse research pipeline." About TP-3654 TP-3654 is an oral investigational inhibitor of PIM1 kinase, which has shown potential antitumor and antifibrotic activity through multiple pathways, including induction of apoptosis in preclinical models.1,2 TP-3654 was observed to inhibit proliferation and increase apoptosis in murine and human hematopoietic cells expressing the clinically relevant JAK2V617F mutation.2 TP-3654 alone and in combination with ruxolitinib showed white blood cell and neutrophil count normalization, and also reduced spleen size and bone marrow fibrosis in JAK2V617F and MPLW515L murine models of myelofibrosis.2 The safety and efficacy of TP-3654 is currently being clinically evaluated in a Phase 1/2 study in patients with intermediate and high-risk myelofibrosis (NCT04176198). The U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation for TP-3654 for the indication of myelofibrosis in May 2022. About DSP-5336 DSP-5336 is an investigational small molecule inhibitor of the menin and mixed-lineage leukemia (MLL) protein interaction. Menin is a scaffold nuclear protein that plays various key roles in biological pathways, including cell growth regulation, cell cycle control, genomic stability, bone development, and hematopoiesis.3,4 In preclinical studies, DSP-5336 has shown selective growth inhibition in human acute leukemia cell lines with KMT2A (MLL) rearrangements or NPM1 mutations.3,5 The safety and efficacy of DSP-5336 is currently being clinically evaluated in a Phase 1/2 dose escalation/dose expansion study in patients with relapsed or refractory acute leukemia (NCT04988555). The FDA granted Orphan Drug Designation for DSP-5336 for the indication of acute myeloid leukemia in June 2022. About Sumitomo Pharma Sumitomo Pharma Co., Ltd. is a global pharmaceutical company based in Japan with key operations in the U.S. (Sumitomo Pharma America, Inc.), Canada (Sumitomo Pharma Canada, Inc.), and Europe (Sumitomo Pharma Switzerland GmbH) focused on addressing patient needs in psychiatry & neurology, oncology, urology, women's health, rare disease, and cell & gene therapies. With several marketed products in the U.S., Canada, and Europe, a diverse pipeline of early- to late-stage assets, and in-house advanced technology capabilities, we aim to accelerate discovery, research, and development to bring novel therapies to patients sooner. For more information, please visit and LinkedIn to follow us. The Sumitomo Pharma icon is a trademark of Sumitomo Pharma Co., Ltd., used under license. SUMITOMO PHARMA is a trademark of Sumitomo Pharma Co., Ltd., used under license. Sumitomo Pharma America, Inc. is a U.S. subsidiary of Sumitomo Pharma Co., Ltd. © 2023 Sumitomo Pharma America, Inc. All rights reserved. References Foulks JM, Carpenter KJ, Luo B, et al. A small-molecule inhibitor of PIM kinases as a potential treatment for urothelial carcinomas. Neoplasia. 2014;16(5):403-412. Dutta A., Nath D, Yang Y, et al. Genetic ablation of Pim1 or pharmacologic inhibition with TP-3654 ameliorates myelofibrosis in murine models. Leukemia. 2022; 36 (3): 746-759. doi: 10.1038/s41375-021-01464-2. Cierpicki T, Grembecka J. Challenges and opportunities in targeting the menin-MLL Interaction. Future Med Chem. 2014; 6(4):447-462. doi:10.4155/fmc.13.214. Matkar S, Thiel A, Hua X. Menin: a scaffold protein that controls gene expression and cell signaling. Trends Biochem Sci. 2013; 38(8):394-402. doi:10.1016/j.tibs.2013.05.005. Kuhn MWM, Song E, Feng Z, et al. Targeting chromatin regulators inhibits leukemogenic gene expression in NPM1 mutant leukemia. Cancer Discov. 2016; 6(10):1166-1181. doi:10.1158/2159-8290.CD-16-0237. SOURCE Sumitomo Pharma America