Science | H3 Biomedicine

Cancer Genomics

Acquired changes of the genome of cancer cells are key in disrupting the physiological function of normal cells of the body and their transformation into fast growing tumors. Genomic alterations in cancer cell have been linked to the induction of uncontrolled growth and survival, but increasingly are also recognized as drivers of additional hallmarks of cancer including immune evasion.

H3 Biomedicine leverages the external and internal cumulative investment in cancer genomics to identify therapeutic targets and biomarkers based on genetic aberrations identified in patient samples. H3’s data sharing platform is enabling all scientist to explore genomic data through a BioIT eco-system consisting of multiple tools and databases that we internally developed. Our team of highly trained computational biologists, equipped with state-of-the-art computational tools and IT infrastructure, work closely with drug discovery teams to adapt and use fit-for-purpose approaches to analyze, interpret and digest new cancer genomic data. We believe data science is an integral part of genomics driven cancer drug discovery.

Modified Cancer Hallmarks Wheel - Modified from Cell, Volume 144, Issue 5, Douglas Hanahan and Robert A. Weinberg, Hallmarks of Cancer: The Next Generation, p646–674, Copyright 2011, with permission from Elsevier. www.sciencedirect.com/science/article/pii/S0092867411001279

Hallmarks of Cancer

Approach

H3 Biomedicine takes a target-centric approach to drug discovery through use of biological proof-of-concept milestones to enable project progression. Our research efforts focus on answering key scientific questions related to modulating a target that will have predictable therapeutic outcomes in patients. Each project starts with a therapeutic hypothesis for a group of patients that can be identified through testing with a companion assay to identify those patients likely to respond. Thus, our approach contrasts with the traditional and inefficient drug-candidate discovery process and ensures a higher likelihood of clinical success.

Our research team uses a deep understanding of cancer genomics and alterations that can impact various hallmarks of cancer to inform on drug target selection. Our drug discovery projects span a range of biological functions including targeting alterations in cancer driver genes, alterations leading to immune evasion and synthetic lethal approaches. We have a deep expertise in defining the role of changes in RNA homeostasis that contribute to cancer, with a particular focus on alterations in RNA splicing. The RNA splicing platform at H3 Biomedicine is an integral part of our research effort and explores approaches to modulate RNA splicing in cancer cells as a novel approach to cancer therapy. Our biological proof-of-concept approach relies on continuous testing of our therapeutic hypothesis in relevant model systems that enables identification of rationally designed drug candidates. We plan to advance our three lead cancer drug candidates into clinical development in 2016–17 in each case accompanied by a companion diagnostic to identify patients for clinical trials.

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Spliceosome

Pipeline

Through its deep understanding of cancer genomics and target-centric drug discovery approach, H3 has assembled a compelling group of drug candidates for precision therapeutics in cancer. H3 is rapidly progressing its lead and discovery projects tailored for genomically defined subsets of cancer patients. By identifying patients most likely to respond to therapy, this approach to cancer drug discovery increases the likelihood of developing powerful new therapeutics and transformative medicines.

Since the initiation of scientific operations in 2012, we have advanced three projects into pre-clinical development and have several additional pipeline programs in discovery. Click below to learn more about our ongoing clinical programs as well as other research into targets of interest to the fields of cancer genomics.

Product Candidates

Preclinical

Phase 1

Phase 2

H3B-8800

H3B-8800 is a potent, selective, and orally bioavailable small molecule modulator of wild-type and mutant SF3b complex. The SF3b complex is a key component of the spliceosome that is found in the nucleus of cells and is responsible for the removal of noncoding introns from a transcribed pre-messenger RNA. Recurrent heterozygous mutations in several core members (SF3B1, U2AF1, SRSF2, ZRSR2) of the spliceosome have been identified in both hematological malignancies, including myelodysplastic syndrome, AML and chronic lymphocytic leukemia, as well as solid tumors such as those found in skin, lung, breast and pancreatic cancers. Mutations in the core spliceosome components lead to aberrant mRNA splicing that may contribute to disease pathogenesis. Preclinical data indicates that H3B-8800 modulates RNA splicing and shows preferential antitumor activity in a range of spliceosome mutant cancer models. Initial clinical development is ongoing in patients with hematological malignancies (e.g. MDS, AML, and CMML) that may carry mutations in the core spliceosome genes and will assess the safety and preliminary efficacy of H3B-8800.

H3B-6527

H3B-6527 is a selective, orally bioavailable, and potent inhibitor of fibroblast growth factor receptor 4 (FGFR4) that is being investigated for the treatment of advanced hepatocellular carcinoma (HCC).

Aberrant signaling through the FGF19-FGFR4 axis has been shown to drive tumor development and dependency in pre-clinical models of HCC. H3B-6527 has shown sustained tumor regressions in several preclinical models of HCC where FGF19-FGFR4 signaling is aberrantly activated. The safety and preliminary efficacy of H3B-6527 will be explored in patients that are selected using a companion diagnostic that identifies HCC with activated FGF19-FGFR4 pathway activity.

H3B-6545

H3B-6545 is an orally bioavailable, potent and selective small molecule modulator of wild-type and mutant Estrogen Receptor (ERα). Mutations in ERα are detected in up to 30% of patients that initially respond but subsequently relapse to anti-endocrine therapies. Current endocrine therapies are only partially effective in the ERα mutant setting and a significant proportion of endocrine-therapy resistant breast cancer metastases continue to remain dependent on ERα signaling for growth/survival indicating a critical need to develop the next generation of ERα antagonists.

Scientists at H3 Biomedicine have discovered a new class of ERα antagonists called Selective Estrogen Receptor Covalent Antagonists (SERCAs) that inactivate the estrogen receptor by targeting a cysteine that is not present in other nuclear hormone receptors. SERCAs have a unique biological and activity profile compared to Selective Estrogen Receptor Modulators (SERMs) and Selective Estrogen Receptor Degraders (SERDs). Preclinical data indicates H3B-6545 inhibits the growth of cell line and patient-derived xenograft models of wild-type and mutant ERα with improved activity over standard-of-care therapies. Initial clinical development will target breast cancer patients with wild-type and mutant ERα and will assess the safety and preliminary efficacy of H3B-6545.

Splicing Programs