The Future of Precision Medicine in Oncology: Targeting Cancer Stem Cells

Candace M. Howard1, Jagan Valluri2 and Pier Paolo Claudio3,4*
1Department of Radiology, University of Mississippi Medical Center, USA
2Department of Biological Sciences, Marshall University, USA
3Department of BioMolecular Sciences, National Center for Natural Products Research, University of Mississippi, USA
4Department of Radiation Oncology, University of Mississippi Medical Center Cancer Institute, USA

*Corresponding author: Pier Paolo Claudio, Department of BioMolecular Sciences and Radiation Oncology,, National Center for Natural Products Research, University of Mississippi, Jackson, MS 39126, USA

Published: 05 Jan, 2017
Cite this article as: Howard CM, Valluri J, Claudio PP. The Future of Precision Medicine in Oncology: Targeting Cancer Stem Cells. Clin Oncol. 2017; 2: 1187.

Keywords: Precision medicine; Personalized medicine; Drug response assay; Chemo-sensitivity assay; Chemo-resistance assay; Cancer stem cells


Precision medicine in oncology has been a popular topic of discussion in the health-care field since US President Barack Obama announced the Precision Medicine Initiative at his 2015 State of the Union address. Precision medicine is focused on identifying which therapies are most effective for individual patients based on the genetic characterization of their cancer [1-3]. Since the late 1990s, the basis of precision medicine has been to develop targeted therapies to inhibit specific molecular pathways involved in tumor growth and dissemination of cancer cells [2].
Cancer, as we know it, is a heterogeneous and progressive genetic disease caused by genetic instability. Genetic instability is an inherent and normal process that transforms a normal cell into a cancer cell. Normal DNA replication, cell division, and repair are not infallible and are influenced by a variety of inherited and environmental factors. Ultimately, cancer growth and progression is the end result of a wide variety of genetic changes that accumulate in the cancer cells over time. Mutations may happen anywhere in genomic DNA of cancer cells; however, only a subset of mutations found within the genomic landscape of cancer is likely to provide a fitness advantage to the cell. These mutations that provide a growth advantage to cancer cells are called driver mutations. The detection of specific gene driver mutations in certain cancers that either stimulate or interrupt important growthregulatory gene pathways has led to a series of studies aimed at identifyingtreatments against these genetic changes and the discovery of targeted therapies. However, the fact that targeted treatment is most successful in a subset of tumors indicates the need for better classification of clinically related molecular tumor phenotypes based on improved understanding of the mutations in relevant genes, especially in those oncogenic driver mutations.
There are two fundamental aspects that we need to consider when we think about targeted anticancer treatments. The first is that targeted therapy, as well as also conventional chemo- and radiation-therapy, are all known to causeadditional accumulation of genetic changes in cancer cells due to their genomic instability. The second is that,intrinsically genetic instability and the accumulation of additional mutations in cancer cells is a way that cancer cells use to adapt to and survive in a hostile environment such as the one created by these treatment modalities. Collectively, all these post therapy-induced additional genetic changes, may happen in a gene or in a group of genes that are located upstream or downstream tothe “driver” mutated gene in a gene pathway, thus causing the targeted treatment to be unfortunately unsuccessful.
Besides the introduction of targeted therapies for cancer, traditional chemotherapy has been largely established on cytotoxic drugs that destroy rapidly dividing cells which are chosen empirically by the treating physicians, and this approach has been used for the past eight decades. Several studies have been performed to develop diagnostic tools to predict effectiveness of chemotherapy [4]. Chemo-Sensitivity and Resistance Assays (CSRA), which measure cell death or lack of cell death by drug-induced apoptosis, are one of such diagnostic tools. Several studies on CSRA focused on ovarian cancer [5-7], gastric cancer [8], colorectal adenocarcinoma [9], breast cancer [10,11], non-small cell lung cancer [12] and small-cell lung cancer [12,13], have followed similar protocols with minor variations in their assay setup. All of these assays, which have been developed in the past 20-30 years, used cultures of bulk tumor cells to determine cytotoxicity and to predict anticancer response.A major breakthrough in the 1990s in the understanding of cancer initiation and progression has been the discovery of a cellular subpopulation with stem cell–like features, commonly referred to as cancer stem cells (CSCs), which is critical for tumorigenesis, treatment resistance and cancer recurrence [14,15]. CSCsshare many properties with normal adult stem cells,have been shown to propagate the parental tumor in animal models, and to be the cause of metastasis[14-17]. Importantly, cancer lethality is mainly due to the onset of distant metastases and their resistance to chemotherapy. Several evidence demonstrated that CSCs are widely protected against commonly used chemotherapeutic agents by means of different mechanisms, including increased expression of ATP-binding cassette drug transporters, augmented ability in DNA damage repair, and activation of PI3K/AKT and Wnt pathways [18]. Because of the presence of therapy resistant CSCs, each time patients are treated they always have a chance to relapse, and their cancer will likely become more resistant to therapy [19].
Of note is that selection of effective chemotherapy is extremely important not only when therapy is first initiated, but for recurrent disease as well. In fact, administration of ineffective anticancer therapy is often associated with unnecessary toxicity and the development of more aggressive cancer cell clones that are resistant to subsequent therapies[20].
Unfortunately, research on CSCs has failed thus far to discover universally clear and informative biomarkers, mutations, or geneexpression patterns [21]. Recently, a new drug response assay has been developed, which is called ChemoID®that tests separately CSCs and bulk of tumor cells. This test has been used effectively to predict the most active chemotherapy agents’ combination to treat individual cancers [22-27]. Targeting CSCs along with the bulk of other cancer cells is a new paradigm in cancer treatment, which is fulfilling the Precision Medicine Initiative that was launched by President Barak Obama in 2015. The ChemoID® drug response assay in a recent prospective study of 41 glioblastoma patients, showed a statistically significant improved response rate (2.2-fold increase) in patients who were given assay-indicated chemotherapy [28] demonstrating that the ability to personalize therapy by providing the treating physician with drug response information on a panel of standard-of-care first and second choice drugs should aid in the selection of most effective chemotherapy for individual patients, thus resulting in improved clinical outcomes.A drug response assay like ChemoID® that targets CSCs may become a very useful tool for optimizing treatment selection especially when first-line therapy fails, and when there are multiple clinically -acceptable and -equivalent treatments available.


  1. Hutchinson L, Romero D. Precision or imprecision medicine? Nat Rev Clin Oncol. 2016; 13: 713.
  2. Deng X, Nakamura Y. Cancer Precision Medicine: From Cancer Screening to Drug Selection and Personalized Immunotherapy. Trends Pharmacol Sci. 2016; 16: 30157-30162.
  3. Millner LM, Strotman LN. The Future of Precision Medicine in Oncology. Clin Lab Med. 2016; 36: 557-573.
  4. Prasad V: Perspective. The precision-oncology illusion. Nature 2016; 537: S63.
  5. Maenpaa JU, Heinonen E, Hinkka SM, Karnani P, Klemi PJ, Korpijaakko TA, et al. The subrenal capsule assay in selecting chemotherapy for ovarian cancer: a prospective randomized trial. Gynecol Oncol. 1995; 57: 294-298.
  6. Suonio E, Lipponen P, Maenpaa J, Syrjanen K, Kangas L, Tuomisto L. Mitotic index in the subrenal capsule assay as an indicator of the chemosensitivity of ovarian cancer. Cancer Chemother Pharmacol. 1997; 41: 15-21.
  7. Von Hoff DD, Kronmal R, Salmon SE, Turner J, Green JB, Bonorris JS, et al. A Southwest Oncology Group study on the use of a human tumor cloning assay for predicting response in patients with ovarian cancer. Cancer. 1991; 67: 20-27.
  8. Wu B, Zhu JS, Zhang Y, Shen WM, Zhang Q. Predictive value of MTT assay as an in vitro chemosensitivity testing for gastric cancer: one institution's experience. World J Gastroenterol. 2008; 14: 3064-3068.
  9. Whitehouse PA, Knight LA, Di Nicolantonio F, Mercer SJ, Sharma S, Cree IA, et al. Heterogeneity of chemosensitivity of colorectal adenocarcinoma determined by a modified ex vivo ATP-tumor chemosensitivity assay (ATP-TCA). Anticancer Drugs. 2003; 14: 369-375.
  10. Cree IA, Pazzagli M, Mini E, Mazzei T, Hunter EM, Sutherland LA, et al. Methotrexate chemosensitivity by ATP luminescence in human leukemia cell lines and in breast cancer primary cultures: comparison of the TCA-100 assay with a clonogenic assay. Anticancer Drugs. 1995; 6: 398-404.
  11. Mehta RS, Bornstein R, Yu IR, Parker RJ, McLaren CE, Nguyen KP, et al. Breast cancer survival and in vitro tumor response in the extreme drug resistance assay. Breast Cancer Res Treat. 2001; 66: 225-237.
  12. Shaw GL, Gazdar AF, Phelps R, Steinberg SM, Linnoila RI, Johnson BE, et al. Correlation of in vitro drug sensitivity testing results with response to chemotherapy and survival: comparison of non-small cell lung cancer and small cell lung cancer. J Cell Biochem Suppl. 1996; 24: 173-185.
  13. Cortazar P, Gazdar AF, Woods E, Russell E, Steinberg SM, Williams J, et al. Survival of patients with limited-stage small cell lung cancer treated with individualized chemotherapy selected by in vitro drug sensitivity testing. Clin Cancer Res. 1997; 3: 741-747.
  14. Sugihara E, Saya H. Complexity of cancer stem cells. Int J Cancer. 2013; 132: 1249-1259.
  15. Colak S, Medema JP. Cancer stem cells--important players in tumor therapy resistance. FEBS J. 2014; 281: 4779-4791.
  16. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997; 3: 730-737.
  17. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994; 367: 645-648.
  18. Maugeri-Sacca M, Vigneri P, De Maria R. Cancer stem cells and chemosensitivity. Clin Cancer Res. 2011; 17: 4942-4947.
  19. Pan ST, Li ZL, He ZX, Qiu JX, Zhou SF. Molecular mechanisms for tumor resistance to chemotherapy. Clin Exp Pharmacol Physiol. 2016.
  20. van Niekerk G, Davids LM, Hattingh SM, Engelbrecht AM. Cancer stem cells: A product of clonal evolution? Int J Cancer. 2016.
  21. Antoniou A, Hebrant A, Dom G, Dumont JE, Maenhaut C. Cancer stem cells, a fuzzy evolving concept: a cell population or a cell property? Cell Cycle. 2013; 12: 3743-3748.
  22. Cortese A, Pantaleo G, Amato M, Lawrence L, Mayes V, Brown L, et al. A new complementary procedure for patients affected by head and neck cancer: Chemo-predictive assay. Int J Surg Case Rep 2016, 26:42-46.
  23. Kelly SE, Di Benedetto A, Greco A, Howard CM, Sollars VE, Primerano DA, et al. Rapid selection and proliferation of CD133+ cells from cancer cell lines: chemotherapeutic implications. PLoS One. 2010; 5: e10035.
  24. Mathis SE, Alberico A, Nande R, Neto W, Lawrence L, McCallister DR, et al: Chemo-predictive assay for targeting cancer stem-like cells in patients affected by brain tumors. PLoS One. 2014; 9: e105710.
  25. Claudio PP, Mathis SE, Nande R, Lawrence L, Alberico A, Julien TJ, et al. ChemoID Assay for Glioblastoma. In: ASCO Annual Meeting. vol. 33, e13028. Chicago; 2015.
  26. Claudio PP, Mathis SE, Nande R, Alberico A, Neto W, Lawrence L, et al. Novel chemosensitivity assay for targeting cancer stem-like cells in brain tumors. In: ASCO Annual Meeting. vol. 32, e13102. Chicago; 2014.
  27. Claudio PP, Valluri J, E Mathis SE, Alberico A, Alberico T, Denvir J, et al. Chemopredictive assay for patients with primary brain tumors. In: ASCO Annual Meeting. vol. 31, abstr 2089. Chicago; 2013.
  28. Howard CM, Valluri J, Alberico A, Julien T, Mazagri R, Marsh R, et al: Prospective Analysis of Chemo-Predictive Assay for Targeting Cancer Stem Cells in Glioblastoma Patients. Cancer Cell Int 2016, in press.