University of California San Francisco
Helen Diller Family Comprehensive Cancer Center

Hematopoietic Malignancies

The Hematopoietic Malignancies Program includes 35 members from 9 academic departments from the UCSF Schools of Medicine and Pharmacy. The overarching goal of the Hematopoietic Malignancies (HE) Program is to improve the outcome of patients with leukemia, lymphoma, and multiple myeloma through basic and translational laboratory studies and clinical investigation.

The Hematopoietic Malignancies Program conducts research under three themes:

  • Theme 1: Gaining a greater understanding of the molecular pathogenesis of hematopoietic malignancies
  • Theme 2: Undertaking translational studies to identify, develop, and optimize treatment options for patients with hematopoietic malignancies
  • Theme 3: Advancing therapeutic interventions and understanding risk factors to improve outcomes in patients with hematopoietic malignancies

Several principles underlie this multi-disciplinary program including the fundamental premise that investigating how normal hematopoietic cells regulate growth, differentiation, and death; and these principles are integral to understanding how these processes are perturbed in cancer. Furthermore, laboratory studies of primary leukemia, lymphoma, and myeloma specimens can provide complementary insights into mechanisms of hematopoietic cell growth and leukemogenesis. Studies of human hematologic cancer specimens and in accurate mouse models are integral for translating research insights into innovative preclinical and clinical trials that are essential for improving the care of patients afflicted with cancer. Applying this philosophy to leukemia, lymphoma, and myeloma has resulted in a program that includes a diverse and highly interactive group of clinical, translational, population sciences, and basic investigators who utilize a variety of experimental methods to conduct studies in normal and malignant hematopoiesis.

Characterizing how normal physiologic processes are perturbed in hematologic malignancies will provide a scientific foundation for rational new strategies to diagnose, prevent, and treat these cancers. Because the molecular alterations that contribute to leukemia, lymphoma, and myeloma are relatively well understood, these malignancies also provide exceptional opportunities to develop animal models for testing new treatment strategies. UCSF investigators have generated a number of relevant mouse models, which are being used to elucidate targets for rational therapeutic intervention, to perform translational preclinical trials, and to characterize mechanisms of drug response and resistance.

The Program has established a highly interactive interdisciplinary approach that includes research efforts directed at gene discovery; modeling leukemia, lymphoma, and myeloma-associated genetic lesions in the mouse; characterizing signal transduction pathways that are crucial for cellular growth control and are perturbed in hematologic cancers; testing experimental therapeutics with molecular analysis to ascertain mechanisms of drug action and drug resistance; and defining environmental risk factors that contribute to the development of hematologic cancers. The Program is built upon extraordinary institutional strengths in basic and population sciences; outstanding clinical programs for the care of patients with leukemia, lymphoma, and myeloma; and a tradition of cross-disciplinary collaborations in scientific investigations.

 

 


Clinical Trial Accruals:   Charalambos Andreadis, MD and HE Program co-leader Thomas Martin, MD led an initiative to develop a more robust, dynamic clinical trials program. This resulted in a substantial increase in the number of patients accrued to interventional clinical trials, from 34 accruals across 17 trials in 2011 to 87 accruals across 26 trials in 2016.

Theme 1: Gaining a greater understanding of the molecular pathogenesis of hematopoietic malignancies

Plasma Cell Malignancies
New member Arun Wiita, MD, PhD was recruited to run the Multiple Myeloma Translational Initiative (MMTI) laboratory. In collaboration with Al Burlingame, PhDJonathan Weissman, PhD; and James Wells, PhD, he used an integrated systems-level examination of transcription, translation, and proteolysis to demonstrate how multiple myeloma cells globally struggle with chemotherapeutic insults before succumbing to apoptosis. Martin in collaboration with Peter Walter, PhDByron Hann, PhDJeffrey Wolf, MD; and Bin Liu, PhD, constructed CD46 antibody-drug conjugates (ADCs) that potently inhibited proliferation of myeloma cell lines while having little effect on normal cells. The CD46-ADC eliminated myeloma growth in an orthometastatic xenograft model and induced selective apoptosis in primary myeloma cells. This CD46-ADC has been licensed to Fortis Therapeutics, and a first-in-human phase I study has been developed with first patient treated expected in Q2 2018 (Rahul Aggarwal, MD, and Sandy Wong, MD). The myeloma group also demonstrated the pre-clinical promise of a novel p97 inhibitor and these data helped inform an ongoing phase I clinical trial at UCSF. Martin and Wolf led early-phase clinical trials of carfilzomib in combination with lenalidomide and low dose dexamethasone, pomalidomide in combination with cyclophosphamide and dexamethasone5 and a phase I study of TAK-228, a dual TORC1/2 inhibitor that was designed in the lab of Kevan Shokat, PhD.

Theme 2: Undertaking translational studies to identify, develop, and optimize treatment options for patients with hematopoietic malignancies

Myeloid Malignancies
Following work in the last grant cycle that defined the most common mechanisms of resistance to BCR-ABL1 kinase inhibitors in chronic myeloid leukemia (CML), Neil Shah, MD, PhD played a key role in the design and execution of a phase I study of ponatinib, and a subsequent registrational phase II study that led to its approval by the US FDA. Shah subsequently validated FLT3-ITD as a therapeutic target in human acute myeloid leukemia (AML), and rekindled interest in developing and evaluating potent FLT3 inhibitors in the clinic, including several clinical trials undertaken by new associate member Catherine Smith, MD through use of the Early Phase Clinical Trials Unit that confirm clinical activity. Kevin Shannon, MD; Scott Kogan, MD; and Benjamin Braun, MD, PhD demonstrated the promise of continuous MEK inhibition for the treatment of an Nf1 mutant murine model of myeloproliferative neoplasm. Shannon also provided compelling evidence that mutant Ras allele burden correlates with both biologic fitness as well as sensitivity to MEK inhibition in vivo.

Theme 3: Advancing therapeutic interventions and understanding risk factors to improve outcomes in patients with hematopoietic malignancies

Lymphoid Malignancies
James Rubenstein, MD, PhD pioneered efforts to improve outcomes in patients with primary CNS lymphoma (PCNSL). Having established the regimen at UCSF, he subsequently led a multicenter NCTN trial that demonstrated that dose-intensive consolidation for PCNSL is feasible and yields rates of progression-free and overall survival at least comparable to those of regimens involving whole brain radiotherapy (WBRT), thereby eliminating the not insignificant side effects associated with WBRT. Markus Müschen, MD, PhD (former member), in collaboration with Huimin Geng, PhD; Mark Ansel, PhD; and Mignon Loh, MD provided evidence that ERK-mediated negative feedback facilitates B-cell transformation, and represents a therapeutic vulnerability in ALL. His group also demonstrated that human ALL can be divided into two subtypes based upon pre-BCR function. Tonic pre-BCR signaling induced activation of BCL-6 which increased pre-BCR transcriptional output. Inhibition of pre-BCR tyrosine kinases reduced BCL-6 expression and selectively killed these cells.18 Müschen also demonstrated that two transcription factors that are commonly deleted in ALL normally function as metabolic gatekeepers by limiting the amount of cellular ATP to levels that are insufficient for malignant transformation.