Time to target Cancer STEM cells

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Dr. Weeks’ Comment: If you have cancer now, your timing is bad. In a few years, the treatment you are currently receiving “the standard of care” will be something which most oncologists share their head in regret at. Why? Because current chemotherapy and radiation do not target the cancer STEM cells (the only really dangerous cells, the only one which metastasize) – current therapy only targets the cancer TUMOR cells.    But the thought leaders are focusing on addressing cancer STEM cells since they know any therapy which does NOT address these truly dangerous cells is stopgap at best and deceptive at worst.  Read this article and ask your oncologist what he or she is doing to combat you cancer STEM cells….
“Increasing research is being aimed at targeting CSCs as opposed to the conventional targeting of homologous tumor cells.”
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 Therapeutics formulated to target cancer stem cells: Is it in our future?
Stephanie Clayton1 and Shaker A Mousacorresponding author1,2
1The Pharmaceutical Research Institute at Albany College of Pharmacy and Health Sciences, One Discovery Drive, Rensselaer, NY, 12144, USA
2College of Medicine, King Saud University, Riyadh, 11461, Saudi Arabia
corresponding authorCorresponding author.
Stephanie Clayton: Stephanie.Clayton@acphs.edu; Shaker A Mousa: shaker.mousa@acphs.edu
Received July 17, 2010; Accepted March 25, 2011.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Cancer Cell Int. 2011; 11: 7.
Published online 2011 March 25. doi:  10.1186/1475-2867-11-7
Abstract
With the political, social and financial drives for cancer research, many advances have been made in the treatment of many different cancer types. For example, given the increase in awareness, early detection, and treatment of breast and prostate cancers, we have seen substantial increases in survival rates. Unfortunately there are some realms of cancer that have not seen these substantial advancements, largely due to their rapid progression and the inability to specifically target therapy.
The hypothesis that cancers arise from a small population of cells, called cancer stem cells (CSCs), is gaining more popularity amongst researchers. There are, however, still many skeptics who bring into question the validity of this theory. Many skeptics believe that there is not a specific subset of cells that originate with these characteristics, but that they develop certain features over time making them more resistant to conventional therapy. It is theorized that many of the relapses occurring after remission are due to our inability to destroy the self-renewing CSCs. This central idea, that CSCs are biologically different from all other cancer cells, has directed research towards the development of therapy to target CSCs directly. The major dilemma in targeting therapy in myeloproliferative disorders, malignancies of the central nervous system or malignancies in general, is the inability to target CSCs as opposed to normal stem cells. However, with the recent advances in the identifications of unique molecular signatures for CSCs along with ongoing clinical trials targeting CSCs, it is possible to use targeted nanotechnology-based strategies in the management of different types of cancers
Introduction
When discussing potential targets for the treatment of cancer today, the conversation will generally lean towards targeted therapy of cancer stem cells (CSCs). With the identification of potential defining characteristics for CSCs, there have also been more questions raised as to which of these characteristics may make better targets. For many years, research seemed to focus on isolating CSCs by specific identifying markers but the research has seemed to shift towards identifying the way in which these stem cells behave that make them different from bulk tumor cells. Limited efficacy has been seen with the use of cell surface markers in clinical trials; however, there have been recent advances that target other aspects such as signaling pathways or genetic alterations seen particularly in CSCs. The following is a review of what information is out there and what seem to be the most promising paths on this journey to identifying therapeutic targets of self-renewing CSC sub-populations.
Identifying Characteristic Cell Surface Markers
Identifying CSCs by their outer appearance or cell surface markers has been focused on by many researchers. The concept of identifying CSCs by these markers is a rational one. The challenge in targeting CSCs is identifying which cell surface markers are going to be the distinguishing factors that will make them a suitable target.
One of the biggest discoveries in the identification of cell surface markers involved leukemic stem cells (LSCs). The discovery of CD34+/CD38- as a cell surface marker on AML leukemic cells gave the first indication that there may be distinguishing cell surface markers that would allow for targeting of CSCs[1,2]. With this identification it was determined that only cells that were located in the CD34+/CD38- population of progenitor cells had the capacity to initiate leukemia in NOD-SCID mice when compared with CD34- and CD34+/CD38+ cells [2]. Upon further investigation it was determined that those cells that expressed CD34 on their cell surface also strongly expressed BCRP, a member of the ABC transporters, which play an important role in dug efflux. It has also been found that BCRP is the key player in drug efflux in AML leukemic cells as opposed to P-gP which is common in many other biological systems [3]. Although identification of this subpopulation is an important discovery in terms of narrowing the search for a viable target, it only gives information that LSCs are derived from a subpopulation of immature bone marrow cells. It did also provide researchers with a definition of CSCs for AML. It identified a separate population within AML cells that were able to cause cancer transplantation into NON-SCID mice. For this reason there has been a movement in cancer research to target subpopulations within the CD34+/CD38- subpopulation in order to further target LSCs (Table ”‹(Table11).
Table 1
Table 1

Cancer Stem Cell molecular signatures in different cancer types: Potential for CSC targeting
Another cell surface marker widely used in the study of AML treatment is CD33, given its extensive expression on LSCs. CD33 is an immunoglobulin that is believed to aid in regulation of cellular differentiation [4]. CD33 has been found to be expressed on 80-90% of leukemic cells in those patients suffering from AML. Not only has CD33 been widely used in research but it has also made it as far as FDA approval [3,5]. Anti-CD33 antibodies have become an important aspect of CSC targeted therapy. A therapy, called Gemtuzumab ozogamacin (GO) or Mylotarg, approved by the FDA in 2000, combines calicheamicin (a cytotoxic antibiotic) with an anti-CD33 antibody. Mylotarg has been approved for use in CD33+ AML patients who are 60 years of age or older, who are not candidates for other cytotoxic chemotherapy but are experiencing 1st relapse. Guidelines for the treatment of elderly patients suffering from AML still indicate the use of intensive chemotherapy as first line in those who are in good enough health to receive it [6]. Those who are candidates for treatment with intensive chemotherapy, such as daunorubicin in combination with cytarabine, generally are less than 70 years of age, have a WBC <100 × 109/l and no adverse cytogenic abnormalities or MDR expression. These general characteristics are reiterated in a study by the Southwest Oncology Group that assessed cytogenic and multidrug resistance subgroups in elderly patients who were refractory to standard chemotherapy treatment [7].
A phase I trial, conducted by Sievers et al., first gave insight into the use of Mylotarg in patients with refractory or relapsed AML [8]. This study investigated the effects of what is now Mylotarg on 40 relapsed AML patients, with a median age of 54. Disappearance of leukemia, among the trial participants, was indicated by absence of leukemic blast cells in the peripheral blood with <5% leukemic blasts present in the bone marrow. Further, complete remission was defined by disappearance of disease plus an ANC > 1,500/ul and a platelet count .100 × 103/ul, without transfusions. Results from this trial showed that 8 of the 40 patients (20%) of those treated with GO experienced complete remission [8]. Table ”‹Table22 illustrates ongoing clinical trials targeting CSC in different cancer types.
Table 2
Table 2

Update on clinical trials for CSC molecular targets
In an interim report for a study comprised of 3 open-labeled, phase II, multicenter trials, performed in 2001, the safety and efficacy of Mylotarg treatment in AML patients experiencing first relapse, was determined [9]. There were 2 types of responses evaluated during this study. A complete response was defined by leukemic blasts absent from the peripheral blood, <5% blasts bone marrow aspirate or biopsy, peripheral blood counts with hemoglobin levels of 9 g/dL or greater, ANC ≥ 1,500/ul and platelet count ≥ 100,00/ul and RBC transfusion independence for 2 weeks and platelet transfusion independence of at least 1 week. There was also a subset of those evaluated who experienced complete response with the exception of full recovery of platelet counts before they required the next treatment(CRp) [9]. The number of people that experienced these responses was combined to determine an overall response rate for the study. This study, composed of 142 CD33+ AML patients with a median age of 61 years, showed that there was an overall response rate of 30% with a median time to response of 60 days. It was also indicated that the median overall survival was 5.9 months [9]. The final report for this study, published in 2005, indicated similar results [10]. The final report showed that among the 277 patients treated with GO, there was a 26% response rate with a median overall survival of 4.9 months.
According to a new phase III trial that studied the effect of GO on AML patients who were in remission, there was no increase in survival rates among those who used GO when compared to no treatment post remission [11]. Patients in this study were composed of those patients who had experienced complete remission who were then offered 3 cycles of GO or no further treatment. The purpose of this study was to investigate whether treatment with GO post remission may be instrumental in preventing relapse among AML patients. This study included 232 patients who were randomized to either the treatment with GO group or the no treatment group (113 patients in GO arm and 119 patients in no treatment arm). Among these patients there were 2 types of induction chemotherapy used in order to obtain the complete remission. These treatments included induction therapy with 45 mg/m2 dose schedule of daunorubicin (days 1, 2, 3) and cytarabine 200 mg/m2 (days 1-7) or induction therapy with daunorubicin 90 mg/m2. Among the treatment and no further treatment arms, there was no statistically significant difference in the amount of patients who used either therapy [11]. As stated, this study showed no statistically significant difference in survival rates between these 2 groups. This study also provided a more lucid adverse effect profile for Mylotarg. Among the adverse effects of fever, sepsis and hepatic and gastrointestinal toxicities, there was also a strong indication of hematologic toxicity, commonly seen in the form of cytopenias [11]. This might not seem all that surprising as they are the all too familiar adverse effects associated with the majority of chemotherapy; however, this is evidence that the common concentration of CD33 on normal cells needs further investigation.
There may be many reasons why there was no statistically significant difference in survival rates seen among those who were treated with GO and those who received no treatment post remission. One reason may have been that there was a decrease in the expression of CD33 on CSCs but another reason may have been due to efflux mechanisms associated with CSCs. A brief report on the phase II trials mentioned previously [9,10] showed a potential correlation between response to GO therapy and P-gP activity [12]. This report evaluated all of the patients who were treated with GO and compared the responders (CR and CRp) to non-responders.
POSTING IS SHORTENED – for full article, see the full article
Study of the role of the microenvironment in terms of LSC survival is very important; however the focus should be more on the communication between the microenvironmentand the stem cells. Until we learn more about the microenvironment’s effect on regular HSCs, targeting of the communication or signaling pathways between them should be considered
Conclusions
The overall goal of cancer therapy is to target the cancer cells only while leaving viable normal cells unscathed. Some types of cancers can make this job seem impossible given the inability to distinguish. However, with current evidence, the future of targeted CSC eradication does not seem like such a daunting task. Although targeting of CSCs by their specific cell surface markers seems like a very logical approach to target therapy, results seem to indicate that other targeting strategies like signaling pathways or microenvironment may offer better results. This is not to say that identification of cell surface markers does not have its place in terms of studying CSCs. If we can identify different populations of cells that exhibit these cell surface markers and identify them as stem cells we can evaluate the effectiveness of new targeting strategies on that population.
By targeting other characteristics of stem cells, such as specific pathways they use or ways they manipulate their environment for survival, benefit can be seen without spending time on research to prove the hypothesis of CSCs. If we can show now that there are cells that have specific behaviors that decrease apoptosis or efflux mechanisms that make them resistant, then we are one step further in finding treatment to destroy them regardless of whether they are CSCs or cells that have obtained certain survival mechanisms through evolution. Table ”‹Table22 summarizes ongoing clinical trials targeting CSC[44].
Increasing research is being aimed at targeting CSCs as opposed to the conventional targeting of homologous tumor cells. With increasing evidence, an intricate puzzle is being pieced together that is revealing an image consistent with targeted CSC therapy using those unique CSC probes in a nanotechnology-based targeted delivery with cytotoxic agents of CSC and cancer cells. In conclusion, targeting CSC, cancer cells, and its associated micro-environment might provide novel strategies in the management of cancer. However, there is a critical need for more direct surrogate markers (imaging of CSC reduction in the tumor microenvironment or reduction of circulating CSC) to assess the direct impact of those CSC targeted therapies in clinical trials listed in Table ”‹Table22.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
SC and SM have equally contributed to the elaboration of the review. SM was the senior author. All authors read and approved the final manuscript.
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