Cambridge Healthtech Institute’s Third Annual
Targeting Cancer Stem Cells
New Opportunities for Oncology Therapeutics
Part of the 21st Annual Molecular Medicine Tri-Conference
February 13-14, 2014 | Westin St. Francis | San Francisco, CA
Cancer stem cells have now been identified in a variety of tumor types, lending further credibility to the "cancer stem cell hypothesis," and the proposed role these cells play in tumorigenesis, metastasis and treatment resistance. Clinical candidates targeting cancer stem cells continue to show efficacy in the treatment of both solid tumors and hematological malignancies. Despite these leaps forward, questions remain around the biology of cancer stem cells, and how best to move forward toward novel therapeutics for cancer. Each year, Targeting Cancer Stem Cells brings together academic researchers advancing our understanding of the basic science of cancer stem cells with scientists leveraging this knowledge to identify druggable targets and develop novel candidates for the next generation of cancer therapeutics.
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Thursday, February 13
7:30 am Registration and Morning Coffee
9:00 Chairperson’s Opening Remarks
9:05 Poised with Purpose: Understanding Cell Plasticity in Cancer
Christine Chaffer, Ph.D., Post-Doctoral Fellow, Robert Weinberg Laboratory, Whitehead Institute for Biomedical Research
Here we demonstrate that basal breast cancer non-CSCs are plastic cell populations that readily switch from a non-CSC-to-CSC state. We identify that maintenance of the ZEB1 promoter in a bivalent chromatin configuration enables these cells to switch to a CSC state. Our findings support a dynamic model where interconversions between a low and high tumorigenic state are common occurrences. Inhibiting non-CSC-to-CSC plasticity should be considered as an important adjuvant for current therapeutic regimens.
9:35 Myeloproliferative Neoplasia Remodels the Endosteal Bone Marrow Niche into a Self-Reinforcing Leukemic Niche
Eric Pietras, Ph.D., Passegue Laboratory, University of California, San Francisco
The bone marrow (BM) niche contains specialized cell types necessary for hematopoietic stem cell (HSC) maintenance. We show that secreted and cell-bound factors overproduced by myeloid cells during myeloproliferative neoplasia (MPN) remodels the BM niche into a fibrotic, self-reinforcing leukemic niche that impairs normal hematopoiesis and favors leukemic stem cell (LSC) function. Targeting this pathological interplay could represent a novel avenue for treatment of MPN-affected patients and prevention of myelofibrosis.
10:05 Progression after Chemotherapy and Cancer Stem Cells
Carlos Cordon-Cardo, M.D., Ph.D., Professor, Pathology, Icahn School of Medicine at Mount Sinai
The CSC model comprises an attractive framework to explain acquired chemotherapy resistance, since chemotherapy resistant CSCs would be expected to be well suited to initiate progressive disease. A recent and growing body of evidence supports the contribution of CSCs to chemotherapy resistance across a range of hematological and solid malignancies. For example, CSCs contribute to chemotherapy resistance in prostate cancer, and targeting prostate CSCs has stimulated therapeutic combination strategies that suppress acquired resistance.
10:35 Coffee Break with Exhibit and Poster Viewing
11:05 Novel Methods for Isolating and in vitro Expanding CSC for HTS Drug Discovery
Steve McClellan, Manager, Research Operations; Chief, Flow Cytometry & Imaging Core Labs; Coordinator, CSC Working Group, Basic & Translational Sciences, Mitchell Cancer Institute
Traditional methods of isolating CSC from fresh tumors have been difficult. Our laboratory has developed new methods to identify CSC that work across most all tumor types, such as the expression of alkaline phosphatase, and live cell mRNA expression of stem cell markers Oct4, Sox2 and Nanog. We will also present data on the development of new techniques to expand CSC in culture, in such quantities that reliable and reproducible HTS using CSC will now be a reality.
11:35 Beyond WNT, Notch and sHH: Novel CSC Targets
Elaine Hurt, Ph.D., Scientist II, MedImmune
CSCs have high expression of several polycomb repressor members, including EZH2, which is thought to hold the cell in an undifferentiated state. We extended these observations into development of a high throughput assay that obviates the need to isolate CSCs. Using our EZH2 assay, we have identified several novel candidate CSC drug targets in two independent target identification campaigns. This talk will briefly describe this assay and focus on its use in identification of both previously known and unique CSC targets.
12:05 pm SIRPaFc: A Novel Biologic Targeting the CD47 “Do Not Eat” Signal on CSCs and Bulk Tumor Cells
Bob Uger, Ph.D., Chief Scientific Officer, Stem Cell Therapeutics
CD47 binds to SIRPα on the surface of macrophages and delivers a “do not eat” signal that suppresses phagocytosis. There is strong evidence that CSCs and bulk tumor cells in many hematopoietic and solid cancers exploit the CD47-SIRPα pathway to escape macrophage-mediated destruction. Blockade of CD47 using SIRPαFc has emerged as a promising strategy to neutralize the suppressive effects of CD47, and is currently being developed as a treatment for AML.
12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own
1:05 Session Break
1:50 Chairperson’s Remarks
1:55 Development of New Therapeutic Agents that Reduce Tumor Initiating Cell Frequency
Tim Hoey, Ph.D., Senior Vice President, Cancer Biology, OncoMed Pharmaceuticals, Inc.
Cancer stem cells (or tumor initiating cells) mediate tumor progression, metastasis, and recurrence after therapy. We have developed new biologic agents that block key CSC pathways including Notch, Wnt and RSPO-LGR. Currently, we have five therapeutics in clinical testing, anti-DLL4 (demcizumab), anti-Notch2/3, anti-Notch1, anti-FZD (vantictumab), and Fzd8-Fc and others in preclinical development. These agents inhibit tumor growth through multiple mechanisms including a reduction of CSC frequency.
2:25 Targeting Ubiquitination Pathways for Cancer Therapy
Hui-Kuan Lin, Ph.D., Associate Professor, Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center
In this talk, I will discuss the role of distinct ubiquitin ligases (E3) in orchestrating non-proteolytic functions in kinase signaling activation. I will also discuss the potential mechanism by which E3 ligases regulate kinase signaling and their role in cancer development. Finally, I will present the evidence that targeting ubiquitination pathways represents a promising therapeutic strategy for cancer stem cells and cancer treatment by using genetic and pharmacological approaches.
2:55 Refreshment Break with Exhibit and Poster Viewing
3:25 BNC101: A Novel Therapeutic Antibody Against LGR5 that Inhibits Tumor Growth and Reduces Frequency of Cancer-Initiating Cells
Christopher L. Reyes, Vice President, Research and Development Biologics, Bionomics
BNC101 is a humanized monoclonal antibody that targets LGR5, a 7-transmembrane receptor that is highly specific to cancer stem cells. In multiple preclinical studies, BNC101 blocks the growth of cancer stem cells derived from primary patient tumors both in vitro and in vivo. Our therapeutic hypothesis is that targeting of CSCs with BNC101 will lead to durable cures in the clinic by eliminating cancer stem cells at the root of cancer.
3:55 Targeting Cancer Stem Cells with 4SC-202 – An Epigenetic Wnt and Hh Inhibitor
Daniel Vitt, Ph.D., CSO, 4SC AG
4SC-202 is a new epigenetic modulator of the Wnt and Hedgehog signaling pathway currently tested in a phase I clinical trial. 4SC-202 inhibits the Wnt signaling pathway by coordinated transcriptional regulation of positive and negative modulators of the signaling cascade, mediated by specific inhibition of LSD1 (KDM1A) and HDAC1, 2 and 3 enzymes. Comparison with other class I specific HDAC inhibitors shows huge differences in gene regulation and mode of action. By inhibition of the Wnt and Hedgehog signaling pathway, 4SC-202 provokes the inhibition of stemness-related properties like anchorage independent growth, spheroid formation, invasion and metastasis. Preliminary data from phase I 'TOPAS' trial and translation of preclinical biomarkers to patient samples will be presented.
4:25 Breakout Discussions
Challenges and Opportunities in Translational Studies for Cancer Stem Cell-Based Therapies
Moderated by Christopher L. Reyes, Vice President, Research and Development Biologics, Bionomics
• Development and use of appropriate pre-clinical models for evaluation of drug efficacy against cancer stem cells
• Translating emerging insights into the dynamic nature of cancer stem cells and impact on clinical development
• Biomarker strategies for therapies targeting cancer stem cell pathways
Links between Epigenetics and Cancer Stem Cells
Moderated by Daniel Vitt, Ph.D., CSO, 4SC AG
• Links between epigenetics and stemness
• ES signatures and epigenetics/plasticity of cancer cells
• Impact on future clinical trials in epigenetics?
• Anything we can learn from new CSC drug discovery for the epigenetic field?
5:25 Close of Day
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