biospaceApril 18, 2018
Tag: H3 Biomedicine , lymphoma
H3 Biomedicine Inc., a clinical stage biopharmaceutical company specializing in the discovery and development of next-generation cancer medicines using its data science and precision chemistry product engine, today announced novel findings from a comprehensive genomic analysis of 6,235 patients across 15 hematologic malignancies. The results include the first-ever observance of recurrent RNA splicing factor mutations in non-Hodgkin’s lymphoma (NHL) and multiple myeloma (MM). While splicing factor mutations have been observed in other hematologic malignancies, including myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML) and chronic lymphocytic leukemia (CLL), the presence of these mutations in NHL and MM has not been reported previously.
Presented today at the 2018 American Association for Cancer Research (AACR) Annual Meeting in Chicago, these new findings demonstrate the continued emergence of splicing factor mutations as a hallmark of dozens of hematologic and solid tumor cancers, their potential role in tumor formation and growth, and, thus, the opportunity to advance a new class of therapies.
At the AACR meeting, Dominic Reynolds, Ph.D., Vice President of Chemistry at H3 Biomedicine, also gave an oral presentation discussing the discovery of H3B-8800, the Company’s first-in-class potent, selective and orally bioavailable small molecule modulator of the SF3b complex currently in Phase I clinical trials in patients with AML, CMML and MDS with splicing factor mutations.
"We continue to uncover new insights into the prevalence of splicing factor mutations across a broad spectrum of hematologic and solid tumor cancers and are leveraging this knowledge for our existing development programs and to inform the discovery of new targets and drugs," said Peter Smith, Ph.D., chief scientific officer at H3 Biomedicine. "For example, our work presented at AACR describes mutations that are addressed by our lead splicing modulator, H3B-8800, which we’re already evaluating in AML, MDS and CMML patients in an ongoing Phase 1 clinical study. These new findings of mutations in non-Hodgkin’s lymphoma and multiple myeloma could expand the addressable patient population for H3B-8800."
Dr. Smith continued, "Beyond our own development efforts, we hope the novel insights from this research will help advance the oncology community’s understanding of the pathogenesis of multiple myeloma and non-Hodgkin’s lymphoma and stimulate new drug discovery programs to help patients whose cancer cannot be effectively treated or cured with existing therapies."
The findings presented today were the result of an ongoing collaboration between H3 Biomedicine and Foundation Medicine Inc. (NASDAQ:FMI) to help advance the discovery and development of precision medicines in oncology. H3 Biomedicine scientists and scientists from Foundation Medicine jointly uncovered the mutations through computational biology based on the genomics data from FoundationOne®Heme, Foundation Medicine’s comprehensive genomic profiling (CGP) assay for hematologic malignancies and sarcomas. H3 Biomedicine is now performing additional translational research to validate the findings.
"Comprehensive genomic profiling (CGP) is a critical tool to drive the discovery and development of precision medicines in both hematologic and solid tumor cancers," said Vincent Miller, M.D., chief medical officer at Foundation Medicine. "The inherent complexity of all cancers mandates the use of an unbiased comprehensive approach in genomic profiling to speed target identification and therapeutic options. These results obtained using FoundationOneHeme and our FoundationCore™ database further underscore that premise. We look forward to understanding how these findings may translate to potential new therapeutic strategies for patients."
About the Findings
H3 Biomedicine and Foundation Medicine scientists surveyed somatic mutations of several splicing factors (SF3B1, SRSF2, U2AF1, ZRSR2, DDX3X, ZMYM3, PCBP1 and U2AF2) in 6,235 patients across 15 hematological malignancies. While these mutations have been observed in MDS, AML, CMML and CLL, the frequency of these mutations in other hematological malignancies was unknown. In the analysis, 405 genes were analyzed by DNA sequencing using FoundationOneHeme,
The researchers, for the first time, identified splicing factor mutations in NHL (13.8%) and MM (9%), including hotspot somatic mutations of SF3B1, U2AF1 and SRSF2, and loss of function or missense mutations in DDX3X.
NHL-Specific Highlights
Among NHL patients, diffuse large B-cell lymphoma (DLBCL) demonstrated the highest frequency of splicing factor mutations, and these patients exhibited increased tumor mutation burden.
The RNA helicase DDX3X (an enzyme implicated in several types of cancer) was the most frequently mutated in NHL.
The majority of mutations were loss of function or missense mutations, suggesting a pathological relevance of DDX3X in lymphoid malignancies.
MM-Specific Highlights
Among MM patients, SF3B1 and SRSF2 were the two most frequently mutated genes, and patients with these mutations also exhibited increased tumor mutation burden.
Although the most common SF3B1 mutation in hematopoietic malignancies is p.K700E, the findings revealed the most frequent SF3B1 mutation in MM is p.K666.
Findings Across All 15 Hematologic Malignancies
Consistent with prior reports, the hematopoietic malignancies that demonstrated the most frequent splicing factor mutations were CMML, MDS, AML and CLL.
In addition to mutations found across the different hematopoietic malignancies in the genes SRSF2, SF3B1, U2AF1 and ZRSR2, the researchers found DDX3X to be the fifth most frequently mutated gene, followed by ZMYM3, PCBP1 and U2AF2, indicating the importance of splicing dysregulation in hematological malignancies.
For additional details, please clink here to review the abstract.
The novel discovery of splicing factor mutations in NHL and MM underscores the potential of H3 Biomedicine’s product engine to identify previously unknown cancer drivers for the discovery and development of next-generation targeted cancer therapies. Splicing modulation is one of several research focus areas for the Company.
About RNA Splicing Factor Mutations
RNA splicing is the biological process by which pre-cursor messenger RNA (pre-mRNA) is edited into a mature messenger RNA (mRNA) and, ultimately, translated into a protein. Splicing factors carry out the editing process. They are responsible for removing introns, which are a part of a pre-mRNA molecule that do not code for proteins. When RNA splicing factors are mutated, normal RNA splicing becomes aberrant, leading to gene and protein expression changes that likely play a role in tumorigenesis.
About H3B-8800 – H3 Biomedicine’s First-in-Class Splicing Modulator
H3 Biomedicine is advancing novel cancer therapies that target core splicing factor mutations. A Phase 1 study is underway in patients with hematologic malignancies for H3B-8800, H3 Biomedicine’s first spliceosome pathway-targeting cancer therapeutic. H3B-8800 is a potent, selective and orally bioavailable small molecule modulator of wild-type and mutant SF3b complex, a splicing factor gene. The Phase 1 study is evaluating the safety and preliminary efficacy of H3B-8800 in patients with myelodysplastic syndromes, acute myeloid leukemia, and chronic myelomonocytic leukemia who carry mutations in splicing factor genes. In February 2018, H3 Biomedicine published preclinical data in Nature Medicine demonstrating that H3B-8800 modulates RNA splicing and shows preferential antitumor activity in a range of spliceosome-mutant cancer models.
About H3 Biomedicine Inc.
H3 Biomedicine, a Cambridge, Massachusetts-based biopharmaceutical company specializing in the discovery and development of precision oncology treatments, was established in 2011 as a subsidiary of Eisai’s U.S. pharmaceutical operation, Eisai Inc. H3 Biomedicine combines long-term vision with operational excellence, leveraging its collaboration with Eisai Co., Ltd., who provides essential research funding and access to the capabilities and resources of a global pharmaceutical company. Using modern synthetic chemistry, chemical biology and human genetics, H3 Biomedicine seeks to bring the next generation of genomics-based cancer treatments to market with the goal of improving the lives of patients
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