ACRI’S Cancer Stem Cells Research

During the last few years, cancer stem cells (CSCs) have been identified in over 60 percent of cancers and are thought to be one of the major engines of metastasis and cancer recurrence. (1)  Studies have shown that even while chemotherapy agents may be killing the sensitive daughter cells, these agents may simultaneously induce the cancer stem cells to mutate, multiply and metastasize. As the population of cancer stem cells grow, the resistance and aggressiveness of the cancer tends to increase.

THE EVIDENCE

As a consequence, there has been intensive research on targeting this subset of tumor cells, including via ACRI’s work. In 2009, MIT’s While Head Institute, under Professor Weinberg, known as the father or modern oncology, conducted a vast study exploring over 1500 molecules that could destroy these specific self-renewing stem cells (2).

Of all of these molecules, an antibacterial called Salinomycin was shown to be the most effective (3). Preclinical and animal trials have confirmed these findings multiple times. (4) Other less potent molecules have been tested and also found to target selectively CSCs. (5)  Some of these trials have been  combined with chemotherapeutic agents in order to increase the cytotoxic bang of these drugs (6).

THE STATE OF CSC RESEARCH AND ACRI’s CONCLUSION

In mainstream cancer research, there are presently 3300  clinical trials on cancer stem cells and-or stem cells related to cancer therapy.  Many of these studies are in vitro and even more involve combination studies with cytotoxic chemotherapy, vaccines and immunotherapy. We have found no credible  human double blind randomized trials with specific plants and cancer stem cells. (22) A few preclinical experimentations in vitro and with animals, but nothing with human clinical trials. Despite different experimentations and peer reviewed studies, including in Nature, (7) today, there also appears to be no human trials for Salinomycin. (8)

 Pending human trials, the antibacterial salinomycin  has been shown in preclinical trials to be the most effective in their targeting both cancer stem cells and …….. With plant-based extracts,  over 20 molecules have been found to work on CTC signaling pathways to contribute in disarming them. But all of these studies that we have found are preclinical.  Although many of these are concentrated extracts that may need special preparation, some are contained in superfoods and plants, the partial list of which can be found in carosell below. From left to right, we have turmeric (cur cumin active molecule), chances skullcap, salinomycin, milk thistle (active molecule sylibinin) and ginger (active molecule, gingol 6). Human clinical trials on these natural molecules would be warranted.

 

 

CAN SALINOMYCIN KILL CANCER STEM CELLS?

Does salinomycin kill cancer stem cells?

It is widely believed that cancers are initiated and maintained by a subpopulation of deadly cells called epithelial “cancer stem cells” (CSCs). These nasty cells seem to be responsible for tumor initiation, cancer cell survival after therapy, metastatic spread and tumor recurrence.[i] If this is true, then the key search in cancer research is not particularly for agents that kill any and all malignant cells, but those that act on these unusual cellular “gangleaders.”

The search for effective agents that kill CSCs has been a slow and frustrating one. These cells are relatively rare in tumors and are difficult to maintain in culture. In fact, some scientists were beginning to believe that CSCs were invulnerable. However, Massachusetts scientists have now come up with a good candidate drug for killing CSCs, a drug called salinomycin. Salinomycin was originally discovered in a culture broth of Streptomyces albus by Japanese scientists in 1974. They initially found that salinomycin had activity against mycobacteria and some fungi, and seemed effective against some infections in poultry.

The anti-CSC nature of salinomycin was discovered in 2009 as part of a survey of 16,000 compounds by Piyush B. Gupta of the Massachusetts Institute of Technology (MIT) and the Broad Institute.[ii] In cultures of breast cancer cells, salinomycin reduced the proportion of CSCs by more than 100-fold compared to the standard anticancer drug, paclitaxel. Breast cancer was inhibited in mice treated with salinomycin and remaining cancer cells showed greater differentiation.

Since that time there have been over 70 scientific articles on the effects of salinomycin in the treatment of cancer, 29 of which have appeared in 2013. PubMed does not list any human studies of salinomycin per se and searches for “salinomycin” in clinicaltrials.gov and ASCO.org turn up nothing. However, the Cambridge-based company VeraStem has initiated trials with a salinomycin-derivative called VS-6063. The company claims that the compound showed a good safety profile in a 46 patient, phase I trial. According to clinicaltrials.gov, Verastim is currently recruiting patients for four clinical trials: in malignant pleural mesothelioma, in combination with paclitaxel in advanced ovarian cancer, in Japanese subjects with non-hematologic cancers, and in patients with KRAS mutant non-small cell lung cancer.

However salinomycin is probably never going to be a magic bullet unto itself. Scientists in Halle, Germany, report:

“Interestingly, an equilibrium seems to exist between CSCs and non-stem cancer cells, and there are indications that CSCs can be recruited from non-stem cancer cells. As a consequence, it may be necessary to combine a therapy targeting CSCs with common chemotherapy that targets the bulk tumor to avoid the regeneration of CSCs.”[iii]

ADVANCES will keep an eye on salinomycin and particularly on the clinical trials of VS-6063 and report on any positive results.
[i] Coghlin C, Murray GI (2010) Current and emerging concepts in tumour metastasis. J Pathol 222: 1–15.

[ii] Gupta PB, Onder TT, Jiang G, et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009;138(4):645–659.

[iii] Dittmer J, Rody A. Cancer stem cells in breast cancer. Histol Histopathol. 2013;28(7):827–838.

 

(22). The search for effective agents that kill CSCs has been a slow and frustrating one, many alternative scientists claim that over twenty plant-based extracts can zap CSC, but most of these are petri dish experiments, so hard evidence is lacking and all the more so that CSCs  are difficult to maintain in culture.  On the other hand, in mainstream scientists are not motivated to invest in natural molecules, while university studies whose scientists are more intellectually motivated have not shown any credible natural molecule anti CSC strategy that would be safe and efficient for humans.

 

For more information, See ACRI’s  advanced cancer research workshop. 

[ultimatecarousels][carouselsimages]http://advancedcancerresearchinstitute.com/wp-content/uploads/2015/10/tumericrootCC.jpg[/carouselsimages][carouselsimages]http://advancedcancerresearchinstitute.com/wp-content/uploads/2015/11/ScutellariabaicalensisflowersCC3.0unported.jpg[/carouselsimages][carouselsimages]http://advancedcancerresearchinstitute.com/wp-content/uploads/2015/11/Salinomycin.png[/carouselsimages][carouselsimages]http://advancedcancerresearchinstitute.com/wp-content/uploads/2015/11/milkthistle.jpg[/carouselsimages][carouselsimages]http://advancedcancerresearchinstitute.com/wp-content/uploads/2015/05/geneginger.jpg[/carouselsimages][/ultimatecarousels]

 

THIS TEXT IS UNDER CONSTRUCTION

REFERENCE AND PRECISION NOTES

 

Phase III Trial of Gemcitabine, Curcumin and Celebrex in Patients With Advance or Inoperable Pancreatic Cancer in Tel Aviv, Israel

 

(3).  Massachusetts scientists have now come up with a good candidate drug for killing CSCs, a drug called salinomycin. Salinomycin was originally discovered in a culture broth of Streptomyces albus by Japanese scientists in 1974. They initially found that salinomycin had activity against mycobacteria and some fungi, and seemed effective against some infections in poultry.

 

(1). The cancer stem cell model suggests that tumor initiation is governed by a small subset of distinct cells with stem-like character termed cancer stem cells (CSCs). CSCs possess properties of self-renewal and intrinsic survival mechanisms that contribute to resistance of tumors to most chemotherapeutic drugs. The failure to eradicate CSCs during the course of therapy is postulated to be the driving force for tumor recurrence and metastasis. Recent studies have focused on understanding the unique phenotypic properties of CSCs from various tumor types, as well as the signaling pathways that underlie self-renewal and drug resistance.”

(2). Salinomycin is an antibacterial and coccidiostat ionophore therapeutic drug. Salinomycin and its derivatives exhibit high antimicrobial activity against Gram-positive bacteria, including the most problematic bacteria strains such as methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE), and Mycobacterium tuberculosis. Salinomycin is inactive against fungi such as Candida and Gram-negative bacteria. [1
Salinomycin has been shown by Piyush Gupta et al. of the Massachusetts Institute of Technology and the Broad Institute to kill breast cancer stem cells in mice at least 100 times more effectively than the anti-cancer drug paclitaxel. The study screened 16,000 different chemical compounds and found that only a small subset, including salinomycin and etoposide, targeted cancer stem cells responsible for metastasis and relapse.[2][3][4][5]
The mechanism of action by which salinomycin kills cancer stem cells specifically remains unknown, but is thought to be due to its action as a potassium ionophore due to the detection of nigericin in the same compound screen. Studies performed in 2011 showed that salinomycin could induce apoptosis of human cancer cells. Promising results from a few clinical pilote studies reveal that salinomycin is able to effectively eliminate CSCs and to induce partial clinical regression of heavily pretreated and therapy-resistant cancers. The ability of salinomycin to kill both CSCs and therapy-resistant cancer cells may define the compound as a novel and an effective anticancer drug.[6][7] It has been also shown that Salinomycin and its derivatives exhibit potent antiproliferative activity against the drug-resistant cancer cell lines.[8] [9] Salinomycin is the key compound in the pharmaceutical company Verastem’s efforts to produce an anti-cancer-stem-cell drug.

(4). EVI SAL The In 2009, a seminal study by  Dr Gupta and colleagues revealed that salinomycin selectively eliminates human breast CSCs in mice. A follow-up publication demonstrated that salinomycin induces massive apoptosis in human cancer cells of different origin that display multiple mechanisms of drug and apoptosis resistance. There has been  growing evidence that salinomycin not only targets CSCs, but also kills more differentiated non-CSC tumor cells and, most importantly, cancer cells that display efficient mechanisms of resistance to cytotoxic drugs, radiation, and induction of apoptosis. Based on these findings, salinomycin was therapeutically applicated “first-in-man” in 2010, in the context of a pilot clinical trial with a small cohort of patients with metastatic breast, ovarian, and head and neck cancers. Cf.  http://www.hindawi.com/

EXHIBIT A

Int J Mol Sci. 2015 Jul 10;16(7):15727-42.
Phytochemicals as Innovative Therapeutic Tools against Cancer Stem Cells.
Scarpa ES1, Ninfali P2.

Abstract

The theory that several carcinogenetic processes are initiated and sustained by cancer stem cells (CSCs) has been validated, and specific methods to identify the CSCs in the entire population of cancer cells have also proven to be effective. This review aims to provide an overview of recently acquired scientific knowledge regarding phytochemicals and herbal extracts, which have been shown to be able to target and kill CSCs. Many genes and proteins that sustain the CSCs’ self-renewal capacity and drug resistance have been described and applications of phytochemicals able to interfere with these signaling systems have been shown to be operatively efficient both in vitro and in vivo. Identification of specific surface antigens, mammosphere formation assays, serial colony-forming unit assays, xenograft transplantation and label-retention assays coupled with Aldehyde dehydrogenase 1 (ALDH1) activity evaluation are the most frequently used techniques for measuring phytochemical efficiency in killing CSCs. Moreover, it has been demonstrated that EGCG, curcumin, piperine, sulforaphane, β-carotene, genistein and the whole extract of some plants are able to kill CSCs. Most of these phytochemicals act by interfering with the canonical Wnt (β-catenin/T cell factor-lymphoid enhancer factor (TCF-LEF)) pathway implicated in the pathogenesis of several cancers. Therefore, the use of phytochemicals may be a true therapeutic strategy for eradicating cancer through the elimination of CSCs.

KEYWORDS:
cancer stem cells; chemoprevention; herbal extracts; metastases; molecular mechanisms; phytochemicals; self-renewal; therapeutic agents

Uploaded on Feb 4, 2009
Learn why Dr. Wicha and other researchers at the Comprehensive Cancer Center believe stem cells are key to treating advanced breast cancer.

 

 

 

Published on Mar 12, 2013
Cancer stem cells, new frontier in cancer research presented by Max Wicha, M.D.

 

 

 

 

Irving Weissman, professor of developmental biology at Stanford University Medical Center, addresses what cancer stem cells are, how they maintain themselves and why they may be resistant to some current treatments. Weissman also talks about the “don’t eat me” signal and how it relates to the growth of certain types of cancer cells. Find out how Stanford scientists and clinicians are working to identifying cancer stem cells in many types of tumors and how they have used that information to develop new therapeutic strategies.

 

 

Uploaded on Nov 14, 2011
Whitehead Institute Member Robert Weinberg’s keynote address from the 2011 Whitehead Colloquium, November 5, 2011.
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