Emerging evidence continues to reveal the critical nature of cancer stem cells (CSCs) as an essential target in the future of oncology drug development. In a recent study directed by Max S. Wicha, M.D., director of the University of Michigan Comprehensive Cancer Center, it was found that antiangiogenic drugs (agents given to decreased blood vessel formation to tumors) increase breast cancer stem cells. Results of the study appear online in the Proceedings of the National Academy of Sciences Early Edition.
Antiangiogenic therapy has been thought to hold tremendous potential for the treatment of several forms of cancer. However, the effectiveness of such treatments, especially within breast cancer patients, considering the two antiangiogenic drugs Avastin (bevacizumab) from Roche Holdings (OTCQX:RHHBY) and SutentÒ (sunitinib) from Pfizer Inc (NYSE:PFE) studied for use in breast cancer treatment, has been called into question.
Recent clinical trials reveal only a limited benefit of these drugs because, although they do achieve inhibition of primary tumor growth, any lasting responses are rare, with only a moderate increase in progression-free survival but little benefit in overall survival of patients. As such, a U.S. Food and Drug Administration panel has recently revoked its approval of bevacizumab for treatment of advanced breast cancer.
Increasing data now indicating that antiangiogenic agents in fact increase metastatic and invasive aspects of breast cancer cells. The above study authors hypothesizes that because we now know that CSCs have tumor-initiating capabilities and a high metastatic potential, the condition created by the administration of antiangiogenic drugs might accelerate tumor growth and metastasis by increasing the CSC population. The findings in this study that treatment with the antiangiogenic agents' sunitinib or bevacizumab leads to an increase in the CSC population provides a potential explanation for the limited clinical effectiveness of these drugs. If this is the case, then improving the clinical efficacy of antiangiogenic treatments will require the combined use of CSC targeting agents.
Although antiangiogenic drugs work well in terms of reducing tumor volume but increase virulence, combining the drugs with CSC-targeting technologies would significantly enhance the therapeutic value of these drugs. Such targeted agents are under development as cited in my January 24th article on leading drug development efforts in this area.
As an example, ICT-107, the lead product of ImmunoCellular Therapeutics (NYSEMKT:IMUC) currently in Phase IIb trial, targets several antigens on cancer stem cells in addition to targeting Her-2 and IL12aR which are present on breast cancer can be combined with antiangiogenic drugs such as Avastin. These combination products, when developed, will no doubt be used in those disease areas where Avastin and other antiangiogeneic drugs are failing alone. ICT-107 has shown in its clinical trials in brain tumors that after vaccination, the level of CSCs (as measured by CD-133 positive cells) go down by 5-10 times. In contrast if you don't treat with vaccine, these levels usually increase by 2-3 times. Based on this clinical evidence, we think there are significant clinical synergies in a combination approach.
ICT-107 targets six different antigens, several of which are expressed on breast, ovarian, brain and other solid cancers. In cases such as breast cancer it clearly opens up a clinical opportunity to demonstrate Avastin can be used again if combined with a CSC targeting approach such as ICT-107 or Oncomed's OMP-21M18 antibody. In conclusion, we should see more activity in CSC space with the validation of Verastem's IPO (NASDAQ:VSTM) and possibly significant interest from big pharma on these products to salvage antiangiogeneisis agents in indications such as breast cancer.
Disclosure: I am long IMUC.OB.