Dr. Omar Abdel-Wahab: 2021 CDP Achievement Award Winner

Dr. Abdel-Wahab was awarded the CDP Clinical Scholar Award in 2016 for his project titled Investigating and Targeting Diverse Kinase Alterations Driving Systemic Histiocytic Neoplasms:

Histiocytic diseases are a group of blood disorders that affect both children and adults and can lead to severe disability and death. Until recently, there were no effective treatments for the more severe forms of these diseases in adults. However, it was recently discovered that about half of these patients have a mutation in a gene called BRAF and that treating these patients with a medicine that blocks this mutation results in astounding benefits for these patients. Unfortunately, half of histiocytosis patients do not have the BRAF mutation and therefore cannot benefit from this breakthrough therapy. We and others have conducted intensive genetic analyses of these “non-BRAF” patients and found that nearly all have mutations in other genes that turn on a single tumor growth pathway. Fortunately, a class of medicines (called “MEK” inhibitors) blocks this pathway and in compassionate use protocols we have provided this drug to 2 adult patients dying from a histiocytic disorder with dramatic resolution of grave symptoms. Based on these data, we believe that MEK inhibition will provide an important new therapy for those patients without the BRAF mutation as well as an opportunity to understand the pathways that drive these disorders in more detail. In this grant we propose to test the effects of the MEK inhibitor, cobimetinib, in a clinical study in these non-BRAF patients and study the biological importance of the diverse non-BRAF mutations in histiocytic disorder patients.

While the award was focused on histiocytosis, funding from the LLS during the award period (2016-2021) allowed his team to advance research across multiple research topics. Some highlights:

• Understanding and targeting systemic histiocytic neoplasms: Dr. Abdel-Wahab and his laboratory worked with a team of collaborators at Memorial Sloan Kettering and internationally to complete a phase II clinical trial of the MEK1/2 inhibitor cobimetinib in adults with BRAFV600 wild-type histiocytosis. These data have resulted in the US FDA awarding Orphan Drug designation for cobimetinib for adults with any form or molecular genotype of histiocytic neoplasm. In parallel, his team completed the largest genomic study of histiocytosis patients which resulted in the discovery of a number of novel driving mutations in the disease, including the first examples of CSF1R activating mutations in any disease.
• Understanding the mechanistic and therapeutic implications of leukemia-associated RNA splicing factor mutations:
  • Since 2016, his laboratory has identified novel mechanisms by which mutations in the RNA splicing factors SF3B1, ZRSR2, and SRSF2 drive leukemia development.
  • In parallel, they worked to identify genetic and pharmacologic vulnerabilities in cancer cells bearing mutations in RNA splicing factors. This effort has motivated clinical trials of the SF3B1 inhibitor H3B-8800, the RBM39 degrader E7820, and PRMT5 inhibitors in myeloid neoplasms with mutations in RNA splicing factors.
  • Finally, Dr. Abdel-Wahab recently completed a study identifying that pharmacologic modulation of RNA splicing results in bona fide splicing derived neoantigens which augment response to immune checkpoint blockade.
• Genomic studies of rare subsets of hematologic malignancies with clinical and/or therapeutic importance: his team has continued to investigate clinical and genetic subsets of hematologic malignancies such as:
  • Genetic analysis of lymphoid neoplasms with mutations in the the nuclear export protein called XPO1. These blood cancers include CLL and certain lymphomas (Hodgkin’s lymphoma and primary mediastinal B cell lymphomas).
  • NTRK fusion hematologic neoplasms: Although TRK inhibitors are approved for pediatric and adult solid tumors, their efficacy in NTRK fusion hematologic malignancies was previously unknown. Performing genomic analysis across more than 7,000 patients with all forms of blood cancer allowed him to identify the functional and therapeutic potential of TRK inhibition in patient derived xenograft (PDX) and preclinical hematologic malignancy models.
  • Hematologic malignancies arising in the setting of germ cell tumors: his team traced the clonal origins of hematologic malignancies arising in the setting of germ cell tumors to cells initiating in the germ cell tumor and identified the genetic characteristics of this unique and prognostically adverse clinical scenario.
• Developing novel mouse models for myeloid and lymphoid leukemias: a number of genetically engineered murine models as well as patient derived xenograft models of MDS, AML, MPN, and histiocytoses.

All corresponding author publications during the award period:

• Diamond, Durham, et al. Nature 2019
• Durham, Lopez-Rodrigo, et al. Nature Medicine 2019
• Fong, et al. Cancer Cell 2019
• Inoue, et al. Nature 2019
• Inoue, et al. Nature Genetics 2021
• Lee, North, et al. Cancer Cell 2018
• Lu, de Neef, Thomas, et al. Cell 2021
• Taylor, et al. JCI 2020
• Taylor, et al. Cancer Discovery 2019
• Taylor, et al. JCI 2018
• Taylor, Mi, et al. Blood 2020
• Wang, Lu, Pastore, et al. Cancer Cell 2019
• Yoshimi, et al. Nature 2019
• Yoshimi, Baslasis, et al. Blood 2017