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Insight & Intelligence : Jun 12, 2009
Opinion: A Stem of Hope for Cancer Treatments
Evidence mounts in favor of therapies targeting cancer stem cells.!--h2>
President Obama’s promise of hope and change came early to stem cell research. Indeed, a friendlier federal funding environment is already enabling more researchers to explore the potential of embryonic stem cells to repair and regenerate the human body. With no evidence of how these stem cells will work in humans, though, or that they will solve more problems than they could create, the first approved stem cell therapy is still years if not decades away. While change will most certainly remain in the stem cell forecast, hope is likely to be more variable.
While headlines have been highlighting the use of stem cells as therapeutic agents, large pharma is showing a growing interest in companies studying cancer stem cells (CSCs) as therapeutic targets. CSCs can be thought of as stem cells gone haywire to produce tumors instead of tissue. Over the last five years, there has been an exponential rise in publications in the CSC arena with findings demonstrating presence of these in almost all cancer types. Given the pace of aggressive clinical developments and wide interest in the burgeoning field, there is reason to have hope in the potential of CSC therapies to change the cancer treatment paradigm.
The evil cousin of stem cells, CSCs are believed to generate tumors in the same way that their relatives generate normal tissue. Although it is not known whether CSCs arise from mutations in normal stem cells or from tumor cells that acquire stem-like properties, a growing body of evidence suggests that they are the root cause of cancer.
CSCs appear to constitute a tiny but deadly portion of the overall tumor mass. One hypothesis for the recurrence of tumors post surgery and despite radiation and chemotherapy is that CSCs can survive treatment and in some cases migrate from the initial tumor site to cause this recurrence. If this turns out to be the case, then targeting and destroying these CSCs will clearly be critical to ensuring long-term cancer-free survival.
Additionally, last July scientists from the University of Michigan Comprehensive Cancer Care Center suggested that the highly effective response of breast cancer patients treated with Genentech’s Herceptin, which is a mAb, may be due to its specificity against HER2 over-expressing breast cancer cells. HER2 is also highly expressed on breast cancer stem cells. So, the antibody is not only targeting breast cancer cells but also cancer stem cells.
Similar converging evidence from other tumor models has spurred a number of companies both large and small to seek innovative biotherapeutics against CSCs. In the last 18 months GSK inked a $1.4 billion deal with OncoMed, and Roche acquired Arius Research for $200 million.
Three Attack Strategies
The use of mAbs as CSC-targeting agents has only recently begun to be explored in clinical trials. Last year, OncoMed initiated a study with its lead candidate, OMP-21M18, to treat previously treated solid tumors with potential applicability in multiple cancers. The target has not been disclosed, but the strength of the preclinical data was sufficiently strong to ink a lucrative deal with GSK. The other mAb that entered the clinic last year was ARH-460-16-2, developed by Arius Research and subsequently acquired by Roche, targeting a variant of CD44 present on cancer stem cells in solid tumors.
There is significant research being done to identify various CSC markers. One of these markers, CD133 (Prominin-1), has been identified as the most important, as it is overexpressed in a large variety of CSCs. In addition, a number of recent studies have demonstrated poor prognosis in brain tumor patients with high concentration of CD133 in primary tumors, suggesting lower odds of survival in cases where CSCs are present.
Seattle Genetics in collaboration with Celera has developed an anti-CD133 antibody conjugated to an immunotoxin. No plans for clinical development have been announced, so it is hard to comment much on this program except to say that the basic idea is to destroy cells that are CD133-positive. However, this creates a potential safety problem, as CD133 is also expressed at reduced levels on a number of normal and stem cells.
One way to overcome this limitation is to require multiple switches before the targeted cells are destroyed. ImmunoCellular Therapeutics has devised a peptide-based vaccine that does exactly that. Cancer cells as well as CSCs express MHC class I molecules, while normal stem cells have very low to no expression of these molecules. ImmunoCellular Therapeutics’ vaccine works by eliciting a cytotoxic T-lymphocyte response specific to MHC class I molecules and targeted at CD133-positive cells. Thus, these CTLs recognize cancer cells and CSCs but not normal stem cells. This has been demonstrated in the in vitro setting so far, and the company plans to file an IND to initiate a clinical trial later this year.
Optimism for CSC-Targeted Therapy
Our understanding of stem cells is in its infancy today, but there can be no doubt about their potential to solve some of the most complicated health problems in both regenerative medicine as well as cancer. Regenerative medicine is much more complicated due to several stages of development that the stem cells have to undergo to regenerate tissue. However, it may be easier to find therapeutic application in cancer, where the goal is to capture and destroy these tumor-initiating stem cells. Based on several encouraging clinical and preclinical studies combined with significant interest from large pharma to acquire these early-stage assets even before they enter the clinic, a bright future may be in store for cancer stem cell therapies.
Manish Singh, Ph.D., is president and CEO of ImmunoCellular Therapeutics.
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