According to the cancer stem cell (CSC) model, tumors are organized in a cellular hierarchy maintained by a subpopulation of cells displaying stem cell properties. These properties include self-renewal (which drives tumorigenesis) and differentiation (which generates the tumor bulk and contributes to cellular heterogeneity).
CSCs were first observed in hematological malignancies but have also been identified in solid tumors of breast, prostate, brain, colon and pancreas. CSCs are thought to be resistant to conventional chemotherapies and this may be why relapse occurs in many patients and this might explain the failure to develop therapies that are consistently able to eradicate solid tumors. Although currently available drugs can shrink metastatic tumors, these effects are usually transient and often do not appreciably extend the life of patients. One reason for the failure of these treatments is the acquisition of drug resistance by the cancer cells as they evolve; another possibility is that existing therapies fail to kill CSCs effectively. Existing therapies have been developed largely against the bulk population of tumor cells because they are often identified by their ability to shrink tumors. Because most cancer cells have limited proliferative potential, an ability to shrink a tumor mainly reflects an ability to kill these cells. It seems that normal stem cells from various tissues tend to be more resistant to chemotherapeutics than mature cell types from the same tissues. The reasons for this are not clear, but may relate to high levels of expression of anti-apoptotic proteins or adenosine triphosphate-binding cassette transporters such as the multidrug resistance gene. If the same were true of CSCs, then one would predict that these cells would be more resistant to chemotherapeutics than tumor cells with limited proliferative potential. Even therapies that cause complete regression of tumors might spare enough CSCs to allow re-growth of the tumors. Therapies that are more specifically directed against CSCs might result in much more durable responses and even cures of metastatic tumors.
There are limited data on the impact of treatment tailoring based on CSC detection. Gene profiling of CSCs could lead to identification of therapeutic targets on CSCs (e.g. hormone receptors (HR), human epidermal growth factor receptor-2 \[HER-2\] expression, epidermal growth factor receptor \[EGFR\] expression), and could represent tumor biopsy in "real time". Several groups showed frequent discordance of HER-2 status between primary tumor and CSCs, and case reports showed clinical utility for the use of trastuzumab-based therapy based on HER-2 CSCs status. Similarly, the hormonal status of CSCs could be different from that of the primary tumor, which could lead to increase the number of patients suitable for endocrine therapy, but also could explain why endocrine therapy fails in a subset of HR positive (HR+) patients. More specifically, a recent observation from Ginestier et al. demonstrated that over expression of chemokine receptor 1 (CXCR-1) is associated with the aldehyde dehydrogenase positive (ALDH+) cells. In breast carcinomas, the ALDEFLUOR+ phenotype shows partial overlap with the CD44+CD24-Lin-CSC phenotype. Cellular hierarchies have been identified in a series of molecularly characterized breast cancer cell lines and it has been demonstrated that these lines contained ALDEFLUOR+ components that were both tumorigenic and metastatic in NOD/SCID mice. Furthermore, previous observations demonstrated that the addition of recombinant interleukin-8 (IL-8) increased the CSC population as well as increasing its propensity for invasion. Moreover, tissue damage induced by chemotherapeutic agents may induce IL-8 as part of the injury response. This suggests that strategies aimed at interfering with the IL 8/CXCR-1 axis may be able to target CSCs, increasing the efficacy of current therapies. This experimental data provides another therapeutic target in breast cancer.
Reparixin seems to be a good candidate for use in breast cancer patients because of its very acceptable toxicity profile shown in the Phase I and II clinical trials conducted so far, along with its observed activity in vitro against breast cancer cell lines and in vivo in tumor xenografts in mice. A phase 1 study is currently underway to study the effects of reparixin in combination with paclitaxel in metastatic breast cancer.
This small pilot study aims at exploring the effects on breast CSC markers as well as the safety and PK profile of orally administered single agent reparixin in HER-2 negative (HER-2-) early breast cancer patients in the 3 weeks prior to surgery.
The study will be performed in the interval between disease diagnosis and planned surgery and may lead to a minimal delay in surgery. This is balanced by the potential benefits of the study by evaluating CSCs and their prognostic importance as well as obtaining information about the impact of reparixin therapy.
