According to the American Cancer Society, approximately 1.6 million new cancer cases are expected to be diagnosed and approximately 577,000 Americans are expected to die from the disease in 2012. The direct medical costs of cancer in 2007 were $103.8 billion and another $123.0 billion can be attributed to indirect costs, such as lost productivity.
With hundreds of billions at stake, it’s not surprising that there is often a tulipomania effect on companies that report significant scientific advances in the treatment of cancer. Many investors recall the meteoric rise and subsequent plummet of EntreMed, Inc.’s (ENMD) stock following reports of the company’s breakthrough in disrupting the growth of blood vessels [angiogenesis] to kill cancer in mice back in 1998.
As spring is around the corner, it seemed an appropriate time to examine Wall Street’s latest tulip obsession, which relates to the potential of targeting cancer stem cells [CSCs] as a novel approach to eradicating the disease. Stem cells are unique due to their ability to self-renew and/or mature into another type of cell with a more specialized function, such as a muscle cell, a red blood cell, or a brain cell. Accordingly, stem cells hold great promise to potentially replace or repair damaged cells or tissues for a wide range of diseases. Genetic mutations or other factors may give rise to CSCs that possess the same capacity for self-renewal and can mature into cancer cells that comprise the tumor.
For example, normal hematopoietic [blood-forming] stem cells have the potential for self-renewal, a property that enables life-long blood production. These particular stem cells give rise to all of the types of red and white blood cells as well as some other types of cells. Underscoring the importance of hematopoietic stem cells, red blood cells only have a lifespan of approximately 120 days and therefore must be completely replaced every four months.
Genetic mutations or other factors, however, may cause hematopoietic stem cells or their progeny to go awry. In 1994, researchers identified a rare population of stem-like cells in the blood of patients with acute myeloid leukemia [AML]. These unique cells represented less than 1% of the total AML cell population found in the blood. When transplanted into mice with impaired immune systems, these rare cells could recapitulate the entire cellular diversity of human AML in the animals. This was the first time that researchers isolated CSCs.
Traditional cancer treatments, such as chemotherapy and radiation, have limited selectivity. They exert their killing effect on rapidly dividing cells and do not discriminate between normal and cancerous targets. In view of the fact that stem cells as a class tend to be relatively dormant, CSCs are unlikely to be destroyed by such therapeutic approaches. In other words, the “seeds” of the tumor may remain intact – able to grow and spread. Eradicating CSCs in addition to other cancerous cells may hold great promise for the treatment of cancer.
Enthusiasm for targeting CSC’s was recently bolstered by the March 1st announcement that Dainippon Sumitomo Pharma Co., Ltd. would acquire privately-held Boston Biomedical, Inc. for up to $2.63 billion. The deal included $200 million upfront, up to $540 million in development milestone payments, and up to $1.89 billion in sales milestone payments. Boston Biomedical’s lead program for inhibiting CSCs in addition to other cancer cells, BBI608, is entering Phase 3 trials in patients with colorectal cancer.
In addition to Boston Biomedical and other programs currently in development by large pharmaceutical companies, the following is a partial list of emerging public companies with programs also targeting the destruction of CSCs for the treatment of cancer:
Geron Corporation (GERN)
After announcing that the company would discontinue development of its human embryonic stem cell programs, Geron is focusing on novel cancer programs, including lead program Imetelstat [GRN163L], a telomerase inhibitor that has been shown to effectively inhibit CSCs from a broad range of tumors. Imetelstat is in Phase 2 trials for non-small cell lung cancer, metastatic breast cancer, essential thrombocythemia and multiple myeloma.
ImmunoCellular Therapeutics Ltd. (IMUC.OB)
ImmunoCellular is developing active immunotherapies that target not only regular tumor cells, but also CSCs. The company’s most advanced product candidate, ICT-107, is a dendritic cell-based vaccine in Phase 2 development for the treatment of glioblastoma multiforme [GBM]. Underscoring interest in therapeutic approaches targeting CSCs, shares of ImmunoCellular are up more than 67% since the start of the year.
Verastem, Inc. (VSTM)
While unusual for a biotechnology company to pursue an initial public offering [IPO] without having a product candidate in human clinical trials, Verastem successfully priced its IPO at $10 in January 2012 and currently has a market capitalization greater than $236 million. According to the prospectus, Verastem has identified a pipeline of small molecule compounds with the potential to target CSCs. The company’s most advanced product candidates are VS-507, VS-4718 and VS-5095. In late 2012, Verastem expect to file an investigational new drug application [IND] with the U.S. Food and Drug Administration [FDA] to initiate a Phase 1 clinical trial of VS-507.
Private companies also working in the area of CSCs include:
Eclipse Therapeutics, Inc.
Eclipse has developed a CSC discovery platform to identify antibody therapeutics that inhibit the growth of cancer stem cells. Eclipse’s lead program is ET-101, a novel therapeutic antibody designed to target CSCs. ET-101 is expected to advance towards human clinical trials by 2013.
Formula’s lead product candidate, FPI-01, is an active immunotherapy in Phase 2 clinical development for the maintenance of first-remission in AML and other cancers that originated at Memorial-Sloan Kettering Cancer Center. The vaccine targets Wilms Tumor 1 [WT1], an antigen ranked first in a list of 75 cancer vaccine target antigens by the National Cancer Institute [NCI] prioritization project. Stem cell expression was among the criteria used to rank the antigens.
KaloBios Pharmaceuticals, Inc.
KaloBios has initiated a Phase 1 dose-escalating clinical trial for KB004, its first-in-class Humaneered™ monoclonal antibody, in EphA3-expressing hematologic malignancies, including chronic myelogenous leukemia, AML, acute lymphocytic leukemia, and myelodysplastic syndromes, who are refractory to, have failed, or have not received standard-of-care treatment. EphA3 is an onco-fetal protein that is expressed in a range of cancers, including hematologic malignancies and possibly on leukemic stem cells. Studies have shown that expression of EphA3, a receptor tyrosine kinase, is associated with B, T and myeloid neoplasms and certain solid tumors. EphA3 appears to be upregulated on tumor cells, including stem cells, tumor stromal cells, and tumor neovasculature. A biomarker assay is being developed to identify EphA3 expression.
OncoMed’s lead CSC therapeutic, OMP-21M18, is a monoclonal antibody designed to block Delta-like ligand 4 [DLL4], an activator of Notch signaling, which is a pathway known to be important in CSCs and cancer. OMP-21M18 has demonstrated single-agent activity in a Phase 1 study in heavily-pretreated solid tumor patients, and is currently advancing into combination studies with standard chemotherapy in advanced non-small cell lung and pancreatic cancers.
Stemica was founded in 2011 to focus on late-breaking cancer biology discoveries pinpointing cancer stem cells as the reason for not being able to currently cure cancer. Stemica is currently developing novel molecules that inhibit these “cancer sleeper cells” in hopes of providing long-term survival for cancer patients.
Lead programs SL-401, which targets IL-3R, and SL-701, which targets multiple defined epitopes, are in Phase 1 and Phase 2 development for the treatment of AML and glioma, respectively. According to the company’s website, Stemline also possesses a landmark portfolio of intellectual property that includes the earliest filings in the CSC field covering CSC-directed therapeutics, diagnostics, and drug discovery.
In conclusion, targeting CSCs may hold great promise for the treatment of cancer following their initial discovery in 1994. Enthusiasm for the approach has been bolstered by the recent $2.3 billion acquisition of Boston Biomedical, which may prove that targeting CSCs is more than a passing phase. Using the breakthrough with anti-angiogenesis approaches to treat cancer as a model, however, it may be too early to determine which programs will ultimately succeed [e.g., Avastin®, bevacizumab] versus those that fail [e.g., endostatin and angiostatin].