Funding opportunities

Preclinical development of a pan Bcl2 inhibitor for cancer stem cell directed therapy

Funding Type: 
Early Translational II
Grant Number: 
TR2-01789
Principle Investigator: 
Funds requested: 
$3 341 758
Funding Recommendations: 
Recommended
Grant approved: 
Yes
Public Abstract: 
Cancer is the leading cause of death for individuals under 85. Relapse and metastatic disease are the leading causes of cancer related mortality. Anti-apoptotic BCL2 family member overexpression has been shown to promote disease progression in both chronic myeloid leukemia (CML) and prostate cancer. Andr., the emergence of cancer stem cells (CSC) promotes apoptosis resistance in the bone marrow metastatic microenvironment. While targeted therapy with BCR-ABL inhibitors has improved survival of patients with chronic phase CML, the prevalence has doubled since 2001 with over 22,000 people living with CML in the US in 2009. Unfortunately, a growing proportion of patients become intolerant or simply cannot afford full dose BCR-ABL inhibitor therapy and thus, progress to advanced phase disease with a 5 year survival rate of less than 30%. Although prostate cancer prevalence was high at 2.26 million in 2007, distant disease was relatively rare at 5%. However, like blast crisis CML, metastatic prostate cancer survival was only 30% over 5 years. Overexpression of B-cell lymphoma/leukemia-2 (BCL2) family genes has been observed in human blast crisis CML and advanced prostate cancer and may fuel CSC survival. Recent RNA sequencing data demonstrate that human CSC express a panoply of anti-apoptotic Bcl-2 isoforms in response to extrinsic signals in vivo, indicating that a pan BCL2 inhibitor will be required to abrogate CSC survival. Through binding and anti-tumor studies, a potent inhibitor of BCL2 pro-survival family proteins, BI-97C1, has been identified which inhibits the binding of BH3 peptides to Bcl-XL, Bcl-2, Mcl-1 and Bfl1-1 with nanomolar IC50 values. Notably, BI-97C1 potently inhibits growth of human prostate cancer in a xenograft model as well as blast crisis CML CSC engrafted in RAG2-/-c-/- mice while exerting minimal cytotoxicity toward bax-/-bak-/- cells. Because BI-97C1 inhibits all six anti-apoptotic Bcl-2 family members including Bcl-2, Mcl-1 (myeloid cell leukemia 1), Bcl-XL (BCL2L1), Bfl-1 (BCL-2A1), Bcl-W (BCL2L2) and Bcl-B (BCL2L10) proteins, with improved chemical, plasma and microsomal stability relative to apogossypol, we anticipate that it will have clinical utility for targeting apoptosis resistant human CSC in two malignancies with proven reliance on BCL2 signaling – blast crisis CML and advanced prostate cancer. Thus, anti-apoptotic BCL2 family member inhibition with BI-97C1 could represent a vital component of a potentially curative strategy for advanced malignancies that may obviate the need for costly continuous tyrosine kinase inhibitor therapy by increasing sensitivity to therapy. Elimination of CSC contributing to therapeutic resistance, the primary cause of cancer death, is of high clinical importance and thus, development of a small molecule pan-BCL2 inhibitor would fulfill a vital unmet medical need, fuel California biotechnology stem cell R&D efforts and decrease health care costs for patients with cancer.
Statement of Benefit to California: 
Cancer is the leading cause of death for individuals under 85 and usually results from metastatic disease in the setting of therapeutic recalcitrance. Anti-apoptotic BCL2 family member overexpression has been shown to promote disease progression in both chronic myeloid leukemia and prostate cancer. Moreover, the emergence of quiescent cancer stem cells promotes apoptosis resistance in the bone marrow niche for. While targeted BCR-ABL inhibition has resulted in improved survival of patients with chronic phase CML, the prevalence has doubled since 2001 with over 22,000 people living with CML in the US in 2009 (http://www.leukemia-lymphoma.org). Unfortunately, a growing proportion of patients become intolerant or simply cannot afford full dose BCR-ABL inhibitor therapy as a result of spiraling annual costs and thus, progress to advanced phase disease with a 5 year survival rate of less than 30%. Although prostate cancer prevalence was high at 2.26 million in 2007, distant disease was relatively rare at 5%. Like CML, metastatic prostate cancer survival was only 30% over 5 years (http://seer.cancer.gov/statfacts/html/prost.html#prevalence <http://seer.cancer.gov/statfacts/html/prost.html#prevalence> ). Like blast crisis CML, prostate cancer progression and metastasis is associated with BCL2 overexpression. Thus, anti-apoptotic BCL2 family member inhibition with BI-97C1 could represent a vital component of a potentially curative strategy for advanced malignancies that may obviate the need for costly continuous tyrosine kinase inhibitor therapy by increasing sensitivity to therapy. Elimination of CSC contributing to therapeutic resistance, the primary cause of cancer death, is of high clinical importance and thus, development of a small molecule pan-BCL2 inhibitor would fulfill a vital unmet medical need, fuel California biotechnology stem cell R&D efforts and decrease health care costs for patients with cancer.
Review Summary: 
This application for a Development Candidate Award focuses on a novel small molecule therapy for blast crisis chronic myeloid leukemia (CML) and prostate cancer. Blast crisis is the final stage of CML, marked by rapid progression and high mortality. The proposed molecule, BI-97C1, targets the B-cell lymphoma/leukemia-2 (BCL2) family of proteins, which are highly expressed on human cancer stem cells (CSCs) and may play a role in their resistance to chemotherapy. The applicant proposes to develop BI-97C1 toward clinical translation in three Specific Aims: (1) to characterize the effects of BI-97C1 on blast crisis CML CSCs in vitro; (2) to test the efficacy of BI-97C1 to eliminate CSCs in a xenograft mouse model of blast crisis CML, alone and in combination with an approved therapy, and examine potential mechanisms of action; and (3) to extend this work to prostate cancer by examining BCL2 family member expression in various biopsies and testing BI-97C1 effect on CSCs in xenograft mouse models of prostate cancer. The reviewers agreed that, if successful, this proposal could have a significant impact on the treatment of CML. Current therapies for CML are not curative, presumably due to a reservoir of leukemic CSCs that can cause relapse. Therefore, development of a drug that can kill dormant CSCs would have a great impact on CML therapy. Reviewers did not find the scientific rationale for the prostate cancer portion of the proposal to be particularly strong. They would have appreciated more specific and compelling evidence for a role of BCL2 family members in prostate CSC survival. Additionally there was doubt among some reviewers that a role for CSCs in prostate cancer has been sufficiently established. Reviewers were enthusiastic about Aims 1 and 2 of the research plan, focused on CML, but raised a number of concerns about Aim 3, focused on prostate cancer. They found the preliminary data supporting the development of BI-97C1 for treatment of CML to be quite strong. Reviewers appreciated that the safety profile appears to be favorable and felt that the molecule could move forward to IND-enabling studies fairly quickly. Their major criticisms of the proposal centered on Aim 3. Reviewers were concerned that the proposed xenograft model may require extensive development and, even then, may not accurately model metastatic prostate cancer. As the applicant acknowledged, chemotherapy-resistant prostate CSCs isolated from bone marrow or bone metastases may not be the same as previously identified prostate CSCs and may require extensive characterization. Further, serial transplantation experiments depend on robust tumor growth as well as isolation of sufficient numbers of CSCs, neither of which has been demonstrated for prostate cancer. Reviewers generally found Aim 3 to be poorly integrated with the rest of the proposal and were not convinced that its experiments would be feasible within the proposed timeline. The reviewers described the Principal Investigator as highly accomplished in the leukemia field with a strong publication record. They appreciated the varied expertise of the assembled research team, as well as the critical industry collaboration. Reviewers did find the budget to be excessive relative to the proposed work however. Overall, while reviewers were strongly supportive of Aims 1 and 2 of this proposal, they raised significant doubts about the feasibility of Aim 3. The reviewers were impressed by the scientific rationale and preliminary data supporting the CML studies and felt that if the proposal were focused on these, the proposed small molecule would have good chance of progressing to the development candidate stage at the end of three years. PROGRAMMATIC REVIEW A motion was made to move this application into Tier 1, Recommended for Funding. The motion specified that the prostate cancer portions of the grant would be excised, which includes a subcontract to the collaborating academic institution, and that the budget be reduced to reflect these changes. It was noted that cancer proposals were not well represented in Tier 1, a programmatic reason to move this application up. One reviewer commented that this proposal represents a nice collaboration between academia and industry. The motion carried.
Conflicts: 
  • Joyce Frey-Vasconcells

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