Efficacy of a novel small-molecule splicing modulator in chronic lymphocytic leukemia (CLL)

Project Summary/Abstract
Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia in Western countries. Despite recent
treatment advances, CLL remains incurable. In the era of emerging targeted therapies, disease progression and
relapse increasingly are key challenges faced by CLL patients. Therefore, there is an ongoing need for the
identification of targetable vulnerabilities in the context of therapeutic resistance in CLL. Our studies, as well as
recent data from others, have identified aberrant splicing as a molecular characteristic of CLL. Our preliminary
data also suggests that the proprietary small-molecule spliceosome modulator sudemycin D6 (SD6; Wildflower
Biopharma, Inc.), which has recently progressed to GLP IND-enabling studies, effectively inhibits CLL cell growth
and induces apoptosis both in vitro and especially in vivo. We also showed that SD6 can overcome pro-survival
and pro-growth signals and markedly enhance the activity of the clinically approved CLL therapies ibrutinib,
idelalisib and venetoclax to induce apoptosis in primary CLL cells co-cultured with bone marrow stromal cells
and T-cell-derived cytokines. Collectively, our preliminary results provide a strong rationale for future clinical
development of spliceosome modulators and potential combination therapies for CLL. The main objective of this
application is to acquire high quality pre-clinical data that supports the first-in-human clinical trial of the novel
splicing modulator SD6 for CLL. Our central hypothesis is that SD6 is able to effectively kill CLL cells with
selectivity relative to normal B and other hematopoietic cells and to lead to disease regression in vivo, as a novel
potentially curative drug for CLL especially when used in combination with other agents. We further hypothesize
that SD6 has significant synergies with FDA-approved CLL drugs at the molecular level and may overcome drug
resistance of the current clinical CLL drugs when used in combination. To test our hypotheses, we propose the
following Specific Aims: 1) Identify and validate novel therapeutic vulnerabilities to spliceosome modulation in
CLL; 2) Determine the synergistic interactions of SD6 with ibrutinib (BTK inhibitor), idelalisib (PI3K inhibitor), and
venetoclax (BCL2 inhibitor) in primary human CLL samples, as well as CLL cell lines harboring drug resistance
mutations; 3) Evaluate the in vivo therapeutic efficacy of SD6 as a single agent or in combination with ibrutinib,
idelalisib, and venetoclax using a syngeneic CLL mouse model. Our long-term goal is to pursue commercial
development of spliceosome modulators for the treatment of CLL and other cancers with splicing-related
susceptibilities.Project Narrative
Notable advances have been achieved in chronic lymphocytic leukemia (CLL) treatment during the past decade.
Unfortunately, therapeutic resistance has emerged as a formidable challenge, making the identification of novel
treatments that induce deeper, more durable remissions a high priority. Of note, aberrant gene splicing has
recently been identified as a characteristic feature of CLL. Importantly, the vast quantitative and qualitative
splicing abnormalities and altered gene expression present in CLL cells are not found in normal cells, leading to
selective sensitivity of the leukemic cells to splicing modulation. This scientific proposal describes preclinical
studies to characterize the anti-CLL efficacy of sudemycin D6 – a proprietary small-molecule splicing modulator
that targets splicing factor 3B subunit 1 (SF3B1) – using CLL cell lines, primary human CLL cells, and a CLL
mouse model. Establishing proof of concept for sudemycin D6 with the studies proposed herein would provide
the basis for clinical development of the small molecule as a novel CLL therapy.