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Author/Curator: Ritu Saxena, PhD

For several decades, research efforts have focused on targeting progression of cancer cells in primary tumors. Primary tumor cell targeting strategies include standard chemotherapy and immunotherapy and modulation of host microenvironment including tumor vasculature. However, cancer progression is comprised of both primary tumor growth and secondary metastasis (Langley RR and Fidler IJ. Tumor cell-organ microenvironment interactions in the pathogenesis of cancer metastasis. Endocr Rev. 2007 May;28(3):297-321; http://www.ncbi.nlm.nih.gov/pubmed/17409287). Owing to the property of unilimited cell division, cells in primary tumor increase rapidly in number and density and are able to favorably influence their microenvironment. Metastasis, on the other hand, depends on the ability of cancer cells to disseminate, circulate, adapt to the harsh environment and seed in different organs to establish secondary tumors. Although tumor cells are shed into the circulation in large numbers since early stages of tumor formation, few tumor cells can survive and proceed to overt metastasis. (Husemann Y et al. Systemic spread is an early step in breast cancer. Cancer Cell. 2008 Jan;13(1):58-68; http://www.ncbi.nlm.nih.gov/pubmed/18167340). Tight vascular wall barriers, unfavorable conditions for survival in distant organs, and a rate-limiting acquisition of organ colonization functions are just some of the impediments to the formation of distant metastasis (Chiang AC and Massagué J. Molecular basis of metastasis. N Engl J Med. 2008 Dec 25;359(26):2814-23; http://www.ncbi.nlm.nih.gov/pubmed/19109576).

It has been hypothesized that metastasis is initiated by a subpopulation of circulating tumor cells (CTC) found in the blood of patients. Therefore, understanding the function of CTC and targeting the CTC is gaining attention as a possible therapeutic avenue in carcinoma treatment.

CTCs

Figure: Circulating tumor cells in the metastatic cascade

(Image source: Chaffer CL and Weinberg RA. Science 2011,331, pp. 1559-1564; http://www.ncbi.nlm.nih.gov/pubmed/21436443)

Isolation of CTC

Initial methods relied on the difference in physical properties of cells. When spun in a centrifuge, different cells in the blood sample settle in separate layers based on their byoyancy, and CTC are found in the white blood cell fraction. Because CTC are generally larger than white blood cells, a size-based filter could be used to separate the cell types (Vona G, et al, Isolation by size of epithelial tumor cells : a new method for the immunomorphological and molecular characterization of circulating tumor cells. Am J Pathol, 2000 Jan;156(1):57-63; http://www.ncbi.nlm.nih.gov/pubmed/10623654).

Herbert A Fritsche, PhD, Professor and Chief, Clinical Chemistry, Department of Laboratory Medicine, The University of Texas, MD Anderson Cancer Center, demonstrated that the CTC can be captured using antibody labeled magnetic beads, either in positive or negative selection schema. After the circulating tumor cells are isolated, they may be characterized by immunohistochemistry and counted.  Alternatively, these cells may be characterized by gene expression analysis using RT-PCR. One of the CTC detection methods, Veridex Inc, Cell Search Assay, has been cleared by the US FDA for use as a prognostic test in patients with metastatic cancers of the breast, prostate and colon. This technology relies on the expression of epithelial cellular adhesion molecular (EpCAM) by epithelial cells and the isolation of these cells by immunomagnetic capture using anti-EpCAM antibodies.  Enriched CTC are identified by immunofluorescence. Martin Fleisher, PhD, Chair, Department of Clinical Laboratories, Memorial Sloan-Kettering Cancer Center discussed in a webinar at the biomarker symposia, Cambridge Healthtech Institute, that every new technology has shortcomings, and the reliance on cancer cells to express sufficient EpCAM to enable capture may affect the role of this technology in future clinical use. Heterogeneous downregulation of epithelial surface antigen in invasive tumor cells has been reported. Thus, alternative methods to detect CTC are being developed. These new methods include-

  1. Flow cytometry that sorts cells by size and surface antigen expression.
  2. CTC microchips that are designed to capture CTC as whole blood flows past EpCAM-coated mirco-posts.
  3. Enrichment by filtration using filters with a pore size of 7-8 µm, that permits smaller red blood cell, leukocytes, and platelets to pass, but captures CTC that have diameters of about 12-15 µm.

Better identification of CTC

Baccelli et al (2013) developed a xenograft assay and demonstrated that the primary human luminal breast cancer CTC contain metastasis-initiated cells (MICs) that give rise to bone, lung and liver metastases in mice. These MIC-containing CTC populations expressed EPCAM, CD44, CD47 and MET. It was observed that in a small cohort of patients with metastases, the number of CTC expressing markers EPCAM,CD44, CD47 and MET, but not of bulk EPCAM+ CTC, correlated with lower overall survival and increased number of metastasic sites. These data describe functional circulating MICs and associated markers, which may aid the design of better tools to diagnose and treat metastatic breast cancer. The findings were published in the Nature Biotechnology journal recently (Baccelli I, et al. Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nature Biotechnology 2013 31, 539–544; http://www.ncbi.nlm.nih.gov/pubmed/23609047).

CTC as prognostic and predictive factor for cancer progression

Martin Fleisher, PhD states “detecting CTC in peripheral blood of patients with cancer has become a clinically relevant and important prognostic biomarker and has been shown to be a predictive biomarker post-therapy. But, key to the use of CTC as a biomarker is the technology designed to enrich cancer cells from peripheral blood.”

Since CTC isolation methods started being established, correlation studies between the cells and a patient’s disease emerged. In 2004, investigators at the Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center (Houston, TX) discovered that the CTC were associated with disease progression and survival in metastatic breast cancer. The clinical trial recruited 177 patients with measurable metastatic breast cancer for levels of CTC both before the patients were to start a new line of treatment and at the first follow-up visit. The progression of the disease or the response to treatment was determined with the use of standard imaging studies at the participating centers. Patients in a training set with levels of CTC equal to or higher than 5 per 7.5 ml of whole blood, as compared with the group with fewer than 5 CTC per 7.5 ml, had a shorter median progression-free survival (2.7 months vs. 7.0 months, P<0.001) and shorter overall survival (10.1 months vs. >18 months, P<0.001). At the first follow-up visit after the initiation of therapy, this difference between the groups persisted (progression-free survival, 2.1 months vs. 7.0 months; P<0.001; overall survival, 8.2 months vs. >18 months; P<0.001), and the reduced proportion of patients (from 49 percent to 30 percent) in the group with an unfavorable prognosis suggested that there was a benefit from therapy.  Thus, the number of CTC was found to be an independent predictor of progression-free survival and overall survival in patients with metastatic breast cancer (Cristofanilli M, et al, Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004 Aug 19;351(8):781-91; http://www.ncbi.nlm.nih.gov/pubmed/15317891).

Similar results have been observed in other cancer types, including prostate and colorectal cancer. The Cell Search System developed by Veridex LLC (Huntingdon Valley, PA) enumerated CTC from 7.5 mL of venous blood and was used to compare the outcomes from three prospective multicenter studies investigating the use of CTC to monitor patients undergoing treatment for metastatic breast, colorectal, or prostate cancer. Evaluation of CTC at anytime during the course of disease allowed assessment of patient prognosis and is predictive of overall survival (Miller MC, et al. Significance of Circulating Tumor Cells Detected by the CellSearch System in Patients with Metastatic Breast Colorectal and Prostate Cancer. J Oncol. 2010; http://www.ncbi.nlm.nih.gov/pubmed/20016752). In addition, the CTC test may permit the oncologist to make an early decision to discontinue first line therapy for metastatic breast cancer and pursue more aggressive alternative treatments.

Genetic analysis of CTC

Additional studies have analyzed the genetic mutations that the cells carry, comparing the mutations to those in a primary tumor or correlating the findings to a patient’s disease severity or spread. In one study, lung cancer patients whose CTC carried a mutation known to cause drug resistance had faster disease progression than those whose CTC lacked the mutation. The investigators analyzed the evolutionary aspect of cancer progression and studied the precursor cells of metastases directly for the identification of prognostic and therapeutic markers. Single disseminated cancer cells isolated from lymph nodes and bone marrow of 107 consecutive esophageal cancer patients were analyzed by whole-genome screening which revealed that primary tumors and lymphatically and hematogenously disseminated cancer cells diverged for most genetic aberrations. Chromosome 17q12-21, the region comprising HER2, was identified as the most frequent gain in disseminated tumor cells that were isolated from both ectopic sites. Furthermore, survival analysis demonstrated that HER2 gain in a single disseminated tumor cell but not in primary tumors conferred high risk for early death (Stoecklein NH, et al. Direct genetic analysis of single disseminated cancer cells for prediction of outcome and therapy selection in esophageal cancer. Cancer Cell. 2008 May;13(5):441-53; http://www.ncbi.nlm.nih.gov/pubmed/18455127).

The abovementioned studies indicate that CTC blood tests have been successfully used to track the severity of a cancer or efficacy of a treatment. In conclusion, the evolution of the CTC technology will be critical in the emerging area of targeted therapy.  With the development and use of new technologies, the links between the genomic information and CTC could be explored and established for targeted therapy.

Challenges in CTC research

  1. Potential clinical significance of CTC has been demonstrated as early detection, diagnostic, prognostic, predictive, surrogate, stratification, and pharmacodynamic biomarkers. Hong B and Zu Y (2013) discuss that “the role of CTC as a disease marker may be unique in different clinical conditions and should be carefully interpreted. A good example is the comparison between the prognostic and predictive biomarkers. Both biomarkers employ progression-free survival and overall survival for data interpretation; however, the prognostic biomarker is independent of specific drug treatment or therapy, and used for the determination of outcomes before treatment, while the predictive biomarker is related to a particular treatment to predict the response. Furthermore, inconsistent results are increasingly reported among the various CTC assay methods, specifically pertaining to results for the CTC detection rate, patient positivity rate, and the correlation between the presence of CTC and survival rate (Hong B and Zu Y. Detecting circulating tumor cells: current challenges and new trends. Source. Theranostics. 2013 Apr 23;3(6):377-94; http://www.ncbi.nlm.nih.gov/pubmed/23781285).
  2. Heterogeneity in CTC along with several other technical factors contribute to discordance, including the changes in methodology, lack of reference standard, spectrum and selection bias, operator variability and bias, sample size, blurred clinical impact with known clinical/pathologic data, use of diverse capture antibodies from different sources, lack of awareness of the pre-analytical phase, oversimplification of the cytopathology process, use of dichotomous decision criteria, etc (Sturgeon C. Limitations of assay techniques for tumor markers. In: (ed.) Diamandis EP, Fritsche HA, Lilja H, Chan DW, Schwartz MK. Tumor markers: physiology, pathobiology, technology, and clinical applications. Washington, DC: AACC Press. 2002:65-82; Gion M and Daidone MG. Circulating biomarkers from tumour bulk to tumour machinery: promises and pitfalls. Eur J Cancer. 2004;40(17):2613-2622; http://www.ncbi.nlm.nih.gov/pubmed/15541962). Therefore, employing a standard protocol is essential in order to minimize a lot of inconsistencies and technical errors.
  3. CTC in a small amount of blood sample might not represent the actual CTC count in the whole blood. In fact, it has been reported that the Cell Search system might undercount the number of CTC. Nagrath et al (2007) have demonstrated that the average CTC number per mL of whole blood is approximately 79-155 in various cancers (Nagrath S, et al. Isolation of rare circulating tumous cells in cancer patients by microchip technology. Nature. 2007;450(7173):1235-1239; http://www.ncbi.nlm.nih.gov/pubmed/18097410). In addition, an investigative CellSearch Profile approach (for research use only) detected an approximately 30-fold higher number of the median CTC in the same paired blood samples (Flores LM, et al. Improving the yield of circulating tumour cells facilitates molecular characterisation and recognition of discordant HER2 amplification in breast cancer. Br J Cancer. 2010;102(10):1495-502; http://www.ncbi.nlm.nih.gov/pubmed/20461092). Such measurement discrepancies indicate that the actual CTC numbers in the blood of patients could be at least 30-100 fold higher than that currently reported by the only FDA-cleared CellSearch system.

Thus, although promising, the CTC technology faces several challenges both in detection and interpretation, which has resulted in its limited clinical acceptance and use. In order to prepare the CTC technology for future widespread clinical acceptance, a comprehensive guideline for all phases of CTC technology development was published by the Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium. The guidelines describe methods for interactive comparisons of proprietary new technologies, clinical trial designs, a clinical validation qualification strategy, and an approach for effectively carrying out this work through a public-private partnership that includes test developers, drug developers, clinical trialists, the FDA and the National Cancer Institute (NCI) (Parkinson DR, et al. Considerations in the development of circulating tumor cell technology for clinical use. J Transl Med. 2012;10(1):138; http://www.ncbi.nlm.nih.gov/pubmed/22747748).

Reference:

  1. Langley RR and Fidler IJ. Tumor cell-organ microenvironment interactions in the pathogenesis of cancer metastasis. Endocr Rev. 2007 May;28(3):297-321; http://www.ncbi.nlm.nih.gov/pubmed/17409287
  2. Husemann Y et al. Systemic spread is an early step in breast cancer. Cancer Cell. 2008 Jan;13(1):58-68; http://www.ncbi.nlm.nih.gov/pubmed/18167340
  3. Chiang AC and Massagué J. Molecular basis of metastasis. N Engl J Med. 2008 Dec 25;359(26):2814-23; http://www.ncbi.nlm.nih.gov/pubmed/19109576
  4. Vona G, et al, Isolation by size of epithelial tumor cells : a new method for the immunomorphological and molecular characterization of circulating tumor cells. Am J Pathol, 2000 Jan;156(1):57-63; http://www.ncbi.nlm.nih.gov/pubmed/10623654
  5. Baccelli I, et al. Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nature Biotechnology 2013 31, 539–544; http://www.ncbi.nlm.nih.gov/pubmed/23609047
  6. Cristofanilli M, et al, Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004 Aug 19;351(8):781-91; http://www.ncbi.nlm.nih.gov/pubmed/15317891
  7. Miller MC, et al. Significance of Circulating Tumor Cells Detected by the CellSearch System in Patients with Metastatic Breast Colorectal and Prostate Cancer. J Oncol. 2010; http://www.ncbi.nlm.nih.gov/pubmed/20016752
  8. Stoecklein NH, et al. Direct genetic analysis of single disseminated cancer cells for prediction of outcome and therapy selection in esophageal cancer. Cancer Cell. 2008 May;13(5):441-53; http://www.ncbi.nlm.nih.gov/pubmed/18455127
  9. Hong B and Zu Y. Detecting circulating tumor cells: current challenges and new trends. Source. Theranostics. 2013 Apr 23;3(6):377-94; http://www.ncbi.nlm.nih.gov/pubmed/23781285
  10. 10. Sturgeon C. Limitations of assay techniques for tumor markers. In: (ed.) Diamandis EP, Fritsche HA, Lilja H, Chan DW, Schwartz MK. Tumor markers: physiology, pathobiology, technology, and clinical applications. Washington, DC: AACC Press. 2002:65-82
  11. Gion M and Daidone MG. Circulating biomarkers from tumour bulk to tumour machinery: promises and pitfalls. Eur J Cancer. 2004;40(17):2613-2622; http://www.ncbi.nlm.nih.gov/pubmed/15541962
  12. Nagrath S, et al. Isolation of rare circulating tumous cells in cancer patients by microchip technology. Nature. 2007;450(7173):1235-1239; http://www.ncbi.nlm.nih.gov/pubmed/18097410
  13. Flores LM, et al. Improving the yield of circulating tumour cells facilitates molecular characterisation and recognition of discordant HER2 amplification in breast cancer. Br J Cancer. 2010;102(10):1495-502; http://www.ncbi.nlm.nih.gov/pubmed/20461092
  14. Chaffer CL and Weinberg RA. Science 2011,331, pp. 1559-1564; http://www.ncbi.nlm.nih.gov/pubmed/21436443

Other related articles on circulation cells as biomarkers published on this Open Access Scientific Journal, include the following:

Blood-vessels-generating stem cells discovered

Ritu Saxena, PhD

https://pharmaceuticalintelligence.com/2012/10/22/blood-vessel-generating-stem-cells-discovered/

Cardiovascular and circulating endothelial cells as BIOMARKERS for prediction of Disease progression risks

Statins’ Nonlipid Effects on Vascular Endothelium through eNOS Activation Curator, Author,Writer, Reporter: Larry Bernstein, MD, FCAP

Cardiovascular Outcomes: Function of circulating Endothelial Progenitor Cells (cEPCs): Exploring Pharmaco-therapy targeted at Endogenous Augmentation of cEPCs Author and Curator: Aviva Lev-Ari, PhD, RN

Vascular Medicine and Biology: Macrovascular Disease – Therapeutic Potential of cEPCs Curator and Author: Aviva Lev-Ari, PhD, RN

Repair damaged blood vessels in heart disease, stroke, diabetes and trauma: Cellular Reprogramming amniotic fluid-derived cells into Endothelial Cells

Reporter: Aviva Lev-Ari, PhD, RN

Stem cells in therapy

A possible light by Stem cell therapy in painful dark of Osteoarthritis” – Kartogenin, a small molecule, differentiates stem cells to chondrocyte, healthy cartilage cells Author and Reporter: Anamika Sarkar, Ph.D and Ritu Saxena, Ph.D.

Human embryonic pluripotent stem cells and healing post-myocardial infarctionAuthor: Larry H. Bernstein, MD

Stem cells create new heart cells in baby mice, but not in adults, study showsReporter: Aviva Lev-Ari, PhD, RN

Stem cells for the rescue of mitochondrial dysfunction in Parkinson’s diseaseReporter: Ritu Saxena, Ph.D.

Stem Cell Research — The Frontier is at the Technion in Israel Reporter: Aviva Lev-Ari, PhD, RN

Research articles by MA Gaballa, PhD

Harris DT, Badowski M, Nafees A, Gaballa MAThe potential of Cord Blood Stem Cells for Use in Regenerative Medicine. Expert Opinion in Biological Therapy 2007. Sept 7(9): 1131-22.

Furfaro E, Gaballa MADo adult stem cells ameliorate the damaged myocardium?. Human cord blood as a potential source of stem cells. Current Vascular Pharmacology 2007, 5; 27-44.

 

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Reporter, Curator: Stephen J. Williams, Ph.D.

KJ Monohan reports in The Family History of Bowel Cancer Clinic blog, a report from the Cancer Research UK about a new program being initiated by a team consisting of The Institute of Cancer Research, The Royal Marsden, Illumina Inc and the Wellcome Trust Centre for Human Genetics to screen ovarian and breast cancer patients for genes known to increase cancer risk.

The program Mainstreaming Cancer Genetics Programme will evaluate 97 known cancer predisposition genes in breast and ovarian cancer patients (using the TruSight Cancer Panel; see below for description and link).

A link to the full story can be found here:

New scheme to routinely test patients for inherited cancer genes.

The program will complement Cancer Research UK’s own stratified medicine program, which aims to identify driver mutations (mutations in genes {usually tumor suppressor genes} which drive (responsible for) the initiation and growth of a patient’s tumor. For descriptions of driver mutations of tumors please see some articles posted on this site such as:

Rewriting the Mathematics of Tumor Growth; Teams Use Math Models to Sort Drivers from Passengers

Winning Over Cancer Progression: New Oncology Drugs to Suppress Passengers Mutations vs. Driver Mutations

 

Writer’s commentary: As I had commented on this posting, 10% of breast and ovarian cancers are considered hereditary, meaning germline mutations exist in cancer risk genes (notably BRCA1/2 for breast /ovarian) and the offspring who inherit these mutant genes from carriers have a greatly enhanced risk to develop cancer in their lifetime. Although not in the scope of this post, I will curate, in a future post, research on the identity and relative risk for various gene mutations for breast/ovarian cancer risk.

TruSight Cancer Panel

A description of Illumina’s TruSight Cancer Panel is given below:

Targeting genes previously linked to a predisposition towards cancer.

  • Developed in collaboration with Professor Nazneen Rahman and team at the Institute of Cancer Research (ICR), London
  • Targets 94 known genes and 284 SNPs associated with a predisposition towards cancer

TruSight Cancer includes genes associated with both common (e.g., breast, colorectal) and rare cancers. In addition, the set includes 284 SNPs found to correlate with cancer through genome-wide association studies (GWAS). Content selection was based on expert curation of the scientific literature and other high-quality resources.

The TruSight Cancer sequencing panel provides custom oligos targeting identified regions of interest. Sufficient product is supplied for four enrichment reactions. TruSight Cancer is compatible with TruSight Rapid Capture and is supported on the MiSeq, NextSeq, and HiSeq sequencing systems.

 

The authors note that in the US and UK, genetic testing is performed at a genetics clinic, at the request of physicians and/or the individual. With the new program the patient’s cancer doctor can manage the genetic testing, giving the oncologist access to critical genetic information which can help in treatment options and family risk assessments.

Some cancer centers already have integrated a genetic counseling department among their services. These departments also act as Family Risk Assessment Programs. A few family risk assessment programs which deal with breast/ovarian cancer are given below:

Fox Chase Cancer Center Risk Assessment Program

The Mariann and Robert MacDonald Women’s Cancer Risk Evaluation Center at Penn Medicine

Massachusetts General Hospital Breast and Ovarian Cancer Genetics and Risk Assessment Program

Breast & Ovarian Risk Evaluation Program at University of Michigan

The Breast & Ovarian Cancer Prevention Program at Seattle Cancer Care Alliance

Dana-Farber Cancer Institute’s Center for Cancer Genetics and Prevention

Cancer Risk Program are offered through the UCSF Medical Center

These are only a few cancer centers in the US which provide comprehensive counseling and testing.

 

Other posts on this site about Cancer Risk and Genetic Testing include:

Testing for Multiple Genetic Mutations via NGS for Patients: Very Strong Family History of Breast & Ovarian Cancer, Diagnosed at Young Ages, & Negative on BRCA Test

(discussions on Angela Jolie’s experiences and issues through genetic testing and decision)

Host – Tumor Interactions during Cancer Therapy – Dr. Yuval Shaked’s Lab @Technion

(discussion by assistant professor on new paradigms in cancer treatment, detection)

Foundation Medicine reported 4,702 Clinical Tests in Q1, 715 were the FoundationOne Heme Cancer Test, average Reimbursement of $3,400 per Test

(report on success and use of Foundation Medicine’s cancer genetic testing kit)

Efficacy of Ovariectomy in Presence of BRCA1 vs BRCA2 and the Risk for Ovarian Cancer

Cancer Biomarkers for Companion Diagnostics

(Scientists from around the world gathered to share some of their newest biomarker research at the “Oncology Biomarkers Conference”)

Invitae been Sued for BRCA1/2 Patent Violation by Myriad Genetics

(legal problems may hinder the availability of BRCA1/2 testing)

Ethical Concerns in Personalized Medicine: BRCA1/2 Testing in Minors and Communication of Breast Cancer Risk

(discussion about issues mothers have informing their daughters about test results)

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Colon Cancer

Author/Editor: Tilda Barliya PhD

 

Colorectal cancer is the third most common type of cancer diagnosed in the United States and is the third most common cause of cancer-related death. The majority of cases are sporadic, with hereditary colon cancer contributing up to 15% of all colon cancer diagnoses. Treatment consists of surgery for early-stage disease and the combination of surgery and adjuvant chemotherapy for advanced-stage disease. Management of metastatic disease has evolved from primary chemotherapeutic treatment to include resection of single liver and lung metastases in addition to resection of the primary disease and chemotherapy (1-4).

Courtesy WebMD site

In the United States, colorectal cancer (CRC) is the third most common type of cancer diagnosed and the third most common cause of cancer-related death in men and women. In 2010, an estimated 102,900 new cases of colon cancer were diagnosed (49,470 male, 53,430 female) and 51,370 patients (26,580 male, 24,790 female) died from CRC. The death rate from colon cancer decreased over the preceding decade, from 30.77 per 100,000 people to 20.5 per 100,000 people. The lifetime risk of developing colon cancer in industrialized nations is 5% and is stable or decreasing. In contrast, the incidence in developing countries continues to rise, hypothesized to be due to increased exposure to risk factors. It has been estimated that 1.5 million people in the United States will be living with CRC by 2020.The financial burden of caring for this population is significant: $4.5 to $9.6 billion per year.

Colon Cancer is divided into 5 types:

  1. Sporadic: 60-85%
  2. Familial: 10-30%
  3. Hereditary non-Polyposis Colon Cancer (HNPCC): 5%
  4. Familial Adenomatous Polyposis (FAP): 1%
  5. Autosomal Dominant Inheritance

The molecular defects are of two types:

  • alterations that lead to novel or increased function of oncogenes
  • alterations that lead to loss of function of tumor-suppressor genes (TSGs)

Multiple genes are associated with the initiation and progression of the different syndromes of colon cancer and are summarized by Fearon ER in Table 1 (6):

Table 1  Genetics of inherited colorectal tumor syndromesa
Syndrome Common features Gene defect(s)
FAP Multiple adenomatous polyps (>100) and carcinomas of the colon and rectum; duodenal polyps and carcinomas; fundic gland polyps in the stomach; congenital hypertrophy of retinal pigment epithelium APC (>90%)
Gardner syndrome Same as FAP; also, desmoid tumors and mandibular osteomas APC
Turcot’s syndrome Polyposis and colorectal cancer with brain tumors (medulloblastomas); colorectal cancer and brain tumors (glioblastoma) APC
MLH1PMS2
Attenuated adenomatous polyposis coli Fewer than 100 polyps, although marked variation in polyp number (from 5 to >1,000 polyps) observed in mutation carriers within a single family APC(predominantly 5′ mutations)
Hereditary nonpolyposis colorectal cancer Colorectal cancer without extensive polyposis; other cancers include endometrial, ovarian and stomach cancer, and occasionally urothelial, hepatobiliary, and brain tumors MSH2
MLH1
PMS2
GTBPMSH6
Peutz-Jeghers syndrome Hamartomatous polyps throughout the GI tract; mucocutaneous pigmentation; increased risk of GI and non-GI cancers LKB1STK11(30–70%)
Cowden disease Multiple hamartomas involving breast, thyroid, skin, central nervous system, and GI tract; increased risk of breast, uterus, and thyroid cancers; risk of GI cancer unclear PTEN (85%)
Juvenile polyposis syndrome Multiple hamartomatous/juvenile polyps with predominance in colon and stomach; variable increase in colorectal and stomach cancer risk; facial changes DPC4 (15%)
BMPR1a(25%)
PTEN (5%)
MYH-associated polyposis Multiple adenomatous GI polyps, autosomal recessive basis; colon polyps often have somatic KRAS mutations MYH

aAbbreviations: FAP, familial adenomatous polyposis; GI, gastrointestinal.

Essentially all of the genes discussed above are conclusively implicated in subsets of CRC due to specific somatic defects that either activate or inactivate gene and protein function. It is hypothesized that essentially any gene with dysregulated expression in CRC—either increased or decreased expression—may have a functionally significant role as an oncogene or a TSG, respectively. The aggregate data on the mutations and function of any given gene must be carefully evaluated to establish whether the gene truly contributes to CRC pathogenesis and whether it should be designated as an oncogene or a TSG (5,6).

The first proposed genetic model of CRC assumed that most CRCs arise from preexisting adenomatous lesions and that the accumulation of multiple gene defects is required for CRCs.

Benign GI tumors are a varied group, but localized lesions that project above the surrounding mucosa are commonly termed polyps. In humans, most colorectal polyps, particularly small polyps less than 5 mm in size, are hyperplastic (6). Most data indicate that hyperplastic polyps are not a major precursor to CRC; rather, the adenomatous polyp, or adenoma, is probably the important precursor lesion (7).

” Adenomas arise from glandular epithelium and are characterized by dysplastic morphology and altered differentiation of the epithelial cells in the lesion. The prevalence of adenomas in the United States is approximately 25% by age 50 and approximately 50% by age 70 (8)”. Only a fraction of adenomas progress to cancer, and progression probably occurs over years to decades. Individuals affected by syndromes that strongly predispose to adenomas, such as FAP, invariably develop CRCs by the third to fifth decade of life if their colons are not removed”.

A more recent and modified version of the genetic model postulate that each gene defect described in the model occurs at high frequency only at particular stages of tumor development. This observation is the basis for assigning a relative order to the defects in a multistep pathway.

Colon Cancer and clinical Trails:

Mutations in the KRAS proto-oncogene are found in 40-45% of patients with CRC and occur mainly in exon 2 (codon 12 and 13) and to a lesser extent in exon 3 (codon 61) and exon 4 (codon 146). A number of studies have evaluated a potential prognostic role of KRAS  in clinical practice for the treatment of colorectal cancer. However, clinical study design, reproducibility, interpretation and reporting of the clinical data remain important challenges.

Laurent-Puig’s group was the first to show the negative predictive value of KRAS mutations for response to the EGFR monoclonal antibody (mAb) cetuximab (11, 12, 13). Ever since then, a number of large phase II-III randomized studies have confirmed the negative predictive value of KRAS mutations for response to cetuximab and panitumumab treatment.

The role of KRAS mutations in predicting response to other therapies remains unclear. A subset analysis of patients treated in the phase III study of bevacizumab plus IFL (irinotecan, bolus 5-FU, and folinic acid) versus IFL showed that the clinical benefit of bevacizumab is independent of KRAS mutational status (11, 14).

The KRAS biomarker story is unique in several ways. It represents the first biomarker integrated into clinical practice in CRC“.

The high prevalence of KRAS mutations in CRC and its strong negative predictive value for EGFR mAb therapies, has led to its rapid acceptance as a valuable biomarker. The EMEA, FDA and ASCO47 now recommend that all patients with metastatic CRC who are candidates for anti-EGFR mAb therapy should be tested for KRAS mutations and, if a KRAS mutation in codon 12 or 13 is detected, then patients should not receive anti-EGFR antibody therapy.

More so, Data from the PETACC-3 trial, presented at ASCO 2010, have shown that KRAS and BRAF mutant CRC tumors induce different gene-expression profiles, further reiterating that these tumors have a distinct underlying biology. Despite intensive progress in the field of genomic research, none of these genomic markers are used routinely in clinical trials.  Only, nowadays, trials are starting to use specific gene-pathway” target in CRC clinical trials.

Samuel Constant et al. Colon Cancer: Current Treatments and Preclinical Models for the Discovery and Development of New Therapies

Summary:

Early studies are underway to understand the role of DNA methylation, chromatin modification, changes in the patterns of mRNA and noncoding RNA expression, and changes in protein expression and posttranslational modification. However,  we do not yet have an indepth and comprehensive understanding of the pathogenesis of the biologically and clinically distinct subsets of CRC. Careful design of clinical trials end points and validation of the genes as potential prognostic markers will allow a better outcome for these patients.

Ref:

1. Sarah Popek, MD, and Vassiliki Liana Tsikitis, MD. Colorectal Cancer: A Review. OncLive  November 10, 2011. http://www.onclive.com/publications/contemporary-oncology/2011/fall-2011/Colorectal-Cancer-A-Review

x. Martin Hefti.,  H.Maximilian Mehdorn., Ina Albert and Lutz Dörner. Fluorescence-Guided Surgery for Malignant Glioma: A Review on Aminolevulinic Acid Induced Protoporphyrin IX Photodynamic Diagnostic in Brain Tumors.  Current Medical Imaging Reviews, 2010, 6, 1-5. http://www.hirslanden.ch/content/global/en/startseite/gesundheit_medizin/mediathek_bibliothek/fachartikel/verschiedenes/fluorescence_guidedsurgeryformalignantglioma/_jcr_content/download/file.res/FluorescenceGuidedSurgeryforMalignantGlioma.pdf

2. Oguz Akin, Sandra B. Brennan., D. David Dershaw., Michelle S. Ginsberg., Marc J. Gollub., Heiko Sch€oder., David M. Panicek, and Hedvig Hricak. Advances in Oncologic Imaging: Update on 5 Common Cancers. CA CANCER J CLIN 2012;62:364–393. http://onlinelibrary.wiley.com/doi/10.3322/caac.21156/pdf

3. O’Donnell, Kevin et al. Nanoparticulate systems for oral drug delivery to the colon. International Journal of Nanotechnology, 2010, 8, 1/2, 4-20. “Colonic Navigation: Nanotechnology Helps Deliver Drugs to Intestinal Target”. http://www.sciencedaily.com/releases/2010/11/101104154553.htm

4. Perumal V. Molecular Therapy and Nanocarrier Based Drug Delivery to Colon Cancer: Targeted Molecular Therapy (AEE788 and Celecoxib) and Drug Delivery (Celecoxib) To Colon Cancer. http://www.amazon.com/Molecular-Therapy-Nanocarrier-Delivery-Cancer/dp/3659162558

5. Xiaoyun Liao, Paul Lochhead, Reiko Nishihara, Teppei Morikawa, Aya Kuchiba, Mai Yamauchi, Yu Imamura, Zhi Rong Qian, Yoshifumi Baba, Kaori Shima, Ruifang Sun, Katsuhiko Nosho, Jeffrey A. Meyerhardt, Edward Giovannucci, Charles S. Fuchs, Andrew T. Chan, Shuji Ogino. Aspirin Use, TumorPIK3CAMutation, and Colorectal-Cancer Survival. New England Journal of Medicine, 2012; 367 (17): 1596 DOI:10.1056/NEJMoa1207756http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3532946/

Gene Mutation Identifies Colorectal Cancer Patients Who Live Longer With Aspirin Therapy. http://www.sciencedaily.com/releases/2012/10/121024175357.htm

6. Fearon ER. Molecular Genetics of Colorectal Cancer. Annual Review of Pathology: Mechanisms of Disease 2011; 6: 479-507.http://www.annualreviews.org/doi/pdf/10.1146/annurev-pathol-011110-130235

7.  Jass JR. 2007. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Hisopathology 50:113–130. http://www.amedeoprize.com/ap/pdf/histopathology.pdf

8.  Rex DK, Lehman GA, Ulbright TM, Smith JJ, Pound DC, et al.  Colonic neoplasia in asymptomatic persons with negative fecal occult blood tests: influence of age, gender, and family history. Am. J. Gastroenterol 1993. 88:825–831.http://www.ncbi.nlm.nih.gov/pubmed/8503374

9. Kerber RA, Neklason DW, Samowitz WS, Burt RW. Frequency of familial colon cancer and hereditary nonpolyposis colorectal cancer (Lynch syndrome) in a large population database. Fam. Cancer 2005; 4:239–44. http://www.ncbi.nlm.nih.gov/pubmed/16136384

10. Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell 1996: 87:159–170. http://users.ugent.be/~fspelema/les%204-5%20HMG/kinzler%20clon.pdf

11. Sandra Van Schaeybroeck, Wendy L. Allen, Richard C. Turkington & Patrick G. Johnston. Implementing prognostic and predictive biomarkers in CRC clinical trials.(colorectal cancer)(Clinical report). Nature Reviews Clinical Oncology 2011: 8; 222-232. http://www.nature.com/nrclinonc/journal/v8/n4/abs/nrclinonc.2011.15.html

12. Lievre, A. et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 66 2006: 3992-3995. http://hwmaint.cancerres.aacrjournals.org/cgi/content/full/66/8/3992

13. Lievre, A. et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J. Clin. Oncol. 2008: 26, 374-379. http://jco.ascopubs.org/content/26/3/374.full.pdf

14. Hurwitz, H. I., Yi, J., Ince, W., Novotny, W. F. & Rosen, O. The clinical benefit of bevacizumab in metastatic colorectal cancer is independent of K-ras mutation status: analysis of a phase III study of bevacizumab with chemotherapy in previously untreated metastatic colorectal cancer. Oncologist  2009: 14, 22-28. http://theoncologist.alphamedpress.org/content/14/1/22.full

Other related articles on this Open Access Online Scientific Journal include the following:

I. By: Aviva Lev-Ari, PhD, RNCancer Genomic Precision Therapy: Digitized Tumor’s Genome (WGSA) Compared with Genome-native Germ Line: Flash-frozen specimen and Formalin-fixed paraffin-embedded Specimen Needed. https://pharmaceuticalintelligence.com/2013/04/21/cancer-genomic-precision-therapy-digitized-tumors-genome-wgsa-compared-with-genome-native-germ-line-flash-frozen-specimen-and-formalin-fixed-paraffin-embedded-specimen-needed/

II. By: Aviva Lev-Ari, PhD, RN. Critical Gene in Calcium Reabsorption: Variants in the KCNJ and SLC12A1 genes – Calcium Intake and Cancer Protection. https://pharmaceuticalintelligence.com/2013/04/12/critical-gene-in-calcium-reabsorption-variants-in-the-kcnj-and-slc12a1-genes-calcium-intake-and-cancer-protection/

III.  By: Stephen J. Williams, Ph.DIssues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing. https://pharmaceuticalintelligence.com/2013/04/10/issues-in-personalized-medicine-in-cancer-intratumor-heterogeneity-and-branched-evolution-revealed-by-multiregion-sequencing/

IV. By: Ritu Saxena, Ph.DIn Focus: Targeting of Cancer Stem Cells. https://pharmaceuticalintelligence.com/2013/03/27/in-focus-targeting-of-cancer-stem-cells/

V.  By: Ziv Raviv PhD. Cancer Screening at Sourasky Medical Center Cancer Prevention Center in Tel-Aviv. https://pharmaceuticalintelligence.com/2013/03/25/tel-aviv-sourasky-medical-center-cancer-prevention-center-excellent-example-for-adopting-prevention-of-cancer-as-a-mean-of-fighting-it/

VI. By: Ritu Saxena, PhD. In Focus: Identity of Cancer Stem Cells. https://pharmaceuticalintelligence.com/2013/03/22/in-focus-identity-of-cancer-stem-cells/

VII. By: Dror Nir, PhD. State of the art in oncologic imaging of Colorectal cancers. https://pharmaceuticalintelligence.com/2013/02/02/state-of-the-art-in-oncologic-imaging-of-colorectal-cancers/

Other posts by the group: Please see https://pharmaceuticalintelligence.com/?s=colon+cancer

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Differentiation Therapy – Epigenetics Tackles Solid Tumors

Author-Writer: Stephen J. Williams, Ph.D.

Genetic and epigenetic events within a cell which promote a block in normal development or differentiation coupled with unregulated proliferation are hallmarks of neoplastic transformation.  Differentiation therapy is a chemotherapeutic strategy directed at re-activating endogenous cellular differentiation programs in a tumor cell therefore driving the cancerous cell to a state closer resembling the normal or preneoplastic cell and therefore incurring loss of the tumorigenic phenotype.

This post will deal with:

  • Agents such as histone deacetylase inhibitors (HDACi), retinoids, and PPARϒ agonists which have been shown to reactivate terminal differentiation programs in solid tumors
  • Clinical trials in solid tumors
  • Issues regarding the use of differentiation therapy in solid tumors

This post is a follow-up post to Histone Deacetylase Inhibitors Induce Epithelial-to-Mesenchymal Transition in Prostate Cancer Cells

To put the need for alternate chemotherapeutic strategies in perspective, one is referred to the National Cancer Statistics from http://www.cancer.gov show that 33% of cancer patients, treated with standard cytolytic chemotherapy, will still die within five years (i.e. one in three will die within 5 years).  However the addition of the differentiation agent retinoic acid to standard chemotherapy regimen for treatment of acute promyelocytic leukemia (APML) had improved 5 year survival rates from a range of 50-80% up to near 90% complete remission rates while 75% become disease free, an astonishing success story.  For a review of APML please be referred to http://en.wikipedia.org/wiki/Acute_promyelocytic_leukemia.  Briefly, APML is predominantly a result of the chromosomal translocation producing a fusion gene between the promyelocytic leukemia (PML) and RARα receptor genes.  The PML-RARα fusion protein recruits transcriptional repressors, histone deacetylases (HDACs), and DNA methyltransferases.  Treatment with pharmacologic doses of retinoic acid dissociates the PML-RARα from HDACs and results in degradation of PML-RARα, eventually resulting in the differentiation of the myeloid cells in APML.

Dr. Igor Matushansky of Columbia University believes such differentiation therapy could be useful in soft tissue sarcomas, due to the existence of a connective tissue (mesenchymal) stem cell,  in vitro methods which can differentiate these cells into mature tissues, and, from a gene clustering analysis his group had performed, correlation of expression signatures of each liposarcoma subtype throughout the adipocytic differentiation spectrum, including early differentiated to more mature differentiated cells(1).   A parallel study by Riester and colleagues had been able to classify breast tumors and liposarcomas along a phylogenetic tree showing solid tumors can be reclassified based on cell of origin via expression patterns(2).  In addition, other solid tumors, such as ovarian cancer are easily classified, based both on pathologic, histologic, and expression analysis into well and poorly differentiated tumors, correlating differentiation status with prognosis.

Compound Classes which have potential in

differentiation therapy for solid tumors

A. Histone Deacetylase Inhibitors (HDACi)

In eukaryotes, epigenetic post-translational modification of histones is critical for regulation of chromatin structure and gene expression.  Histone deacetylation leads to chromatin compaction and is associated with transcriptional repression of tumor suppressors, cell growth and differentiation.  Therefore, HDACi are promising anti-tumor agents as they may affect the cell cycle, inhibit proliferation, stimulate differentiation and induce apoptotic cell death (3). In a review by Kniptein and Gore, entinostat was found to be a well-tolerated HDACi that demonstrates promising therapeutic potential in both solid and hematologic malignancies(4). The path to the discovery of suberoylanilide hydroxamic acid (SAHA, vorinostat) began over three decades ago with our studies designed to understand why dimethylsulfoxide causes terminal differentiation of the virus-transformed cells, murine erythroleukemia cells. SAHA can cause growth arrest and death of a broad variety of transformed cells both in vitro and in vivo at concentrations that have little or no toxic effects on normal cells (for references see (5). In fact, treatment of MCF-7 breast carcinoma cells with SAHA resulted in morphologic changes resembling epithelial mammary differentiation(6).

HDAC inhibitors

Figure.  Structures of some HDACi used in clinical trials for cancer (see section below)

hdacwithsaha

Figure.  HDAC with SAHA

B. Retinoids

Vitamin A and retinoids play significant roles in basic physiological processes such as vision, reproduction, growth, development, hematopoiesis and immunity (7). Retinoids are the natural derivatives and synthetic analogs of vitamin A. They have been shown to prevent mammary carcinogenesis in rodents (8), to inhibit the growth of human cancer cells in vitro  (9,10) and be effective chemopreventive and chemotherapeutic agents in a variety of human epithelial and hematopoietic tumors (11-14).

Retinoids cannot be synthesized de novo by higher animals and consequently must be consumed in the diet. The two sources of retinoids are animal products that contain retinol and retinyl esters, and plant-derived carotenoids (provitamin A). b-carotene is the most potent vitamin A precursor and has been shown to be an active inhibitor of both tumor initiation and promotion (15).

A major function of retinol, relevant to cancer, is its function as an antioxidant. The antioxidant properties of vitamin A have been shown both in vitro and in vivo (16,17). Retinol deficiency causes oxidative damage to liver mitochondria in rats that can be reversed by vitamin A supplementation (18). A caveat to this is in vitro and in vivo evidence of chronic hypervitaminosis A inducing oxidative DNA damage, as well (19-21). Therefore, it is evident that maintaining the vitamin A concentration within a physiological range is critical to normal cell function because either a deficiency or an excess of vitamin A induces oxidative stress (22). Retinoic acids (RA) (all-trans, 9-cis and 13-cis) are the major biologically active retinoids and exert their effects by regulation of gene expression by binding two families of ligand-activated nuclear retinoid receptors (23). Retinoic acid receptors (RARs) and retinoid X receptors (RXRs) regulate the transcription of a large number of target genes that contain retinoic acid response elements (RAREs) in their promoters. Many of these genes are involved in cancer (13,24) and differentiation (24-26).

Several lines of evidence suggest involvement of defects in retinol signaling in cancer, from the observation that a vitamin A-deficient (VAD) diet leads to an increase in the number of spontaneous and chemically induced tumors in animals (27-29) to the observation that RA itself can induce  differentiation and inhibit the growth of many tumor cells (30-32), as well as the identification that components of the RA signaling pathway are absent in cancer cells (33). Vitamin A and its metabolites have been proposed to have a dual effect in cancer prevention, as antioxidants (16,17,19,34) and differentiating agents (35-37). as it is well accepted that retinoid signaling is integral in maintaining the differentiated state of many cell types (13,38). Additionally, current rationale for chemoprevention with retinoids is based, in part, on the hypothesis that some tumors, may arise due to loss of normal somatic differentiation during tissue repair.

C. PPARϒ Agonists

Peroxisome proliferator-activated receptor ϒ (PPARϒ) is a member of the steroid hormone receptor superfamily that responds to changes in lipid and glucose homeostasis but has increasing roles in differentiation and tumorigenesis. The first PPAR (PPARα) was discovered during the search of a molecular target for a group of agents then referred to as peroxisome proliferators, as they increased peroxisomal numbers in rodent liver tissue, apart from improving insulin sensitivity.  One of the first agents, developed in the early 80’s for treatment of hyperlipidemia and hperlipoproteinemia, was clofibrate.  All PPAR subtypes heterodimerize with the retinoid-x-receptor (RXR) and, upon binding of ATRA, activate target genes.

PPARϒ agonists have shown potential as a therapeutic in a variety of cancer types including bladder cancer (39), colon cancer(40),  breast cancer(41), prostate cancer(42).  There are numerous studies showing that PPARϒ agonists have anti-tumorigenic activity via anti-proliferative, pro-differentiation and anti-angiogenic mechanisms of action(43). For example, Papi et al. observed that agonists for the retinoid X receptor (6-OH-11-O-hydroxyphenanthrene), retinoic acid receptor (all-trans retinoic acid (RA)) and peroxisome proliferator-activated receptor (PPAR)-γ (pioglitazone (PGZ)), reduce the survival of MS generated from breast cancer tissues and MCF7 cells, but not from normal mammary gland or MCF10 cells(44) with concomitant upregulation of differentiation markers.

A great website for further information on PPAR is Dr. Jack Vanden Heuvel, Professor of Toxicology at Penn State University at http://ppar.cas.psu.edu/general_information.html.

D. Trabectedin

Trabectedin (ecteinascidin-743 (ET-743); Yondelis) is derived from the Caribbean tunicate Ecteinascidia turbinacta has antitumor activity by binding to the DNA minor groove thus disrupting binding of transcription factors and inhibiting DNA synthesis.  However, it has also been shown, in myxoid liposarcoma (MLS) cells, to cause dissociation of transcription factor TLS-CHOP from promoter sequences resulting in downregulation of target genes such as CHOP, PTX3 and FN1 and induces an adipogenic differentiation program by enhancing activation of CAAT/enhancer binding protein (C/EBP) family of genes.  In MLS, TLS-CHOP sequesters C/EBPβ resulting in block of differentiation programs while trabectedin disrupts this association freeing up C/EBPβ to act as transcriptional activator of genes related to differentiation.

Ongoing Cancer Clinical Trials with HDAC Inhibitors

The following is a listing of some clinical trials using histone deacetylase inhibitors in combination with approved chemotherapeutics in various tumors.  This data was taken from the New Medicine Oncology Knowledge Base ( at http://www.nmok.net).

hdactrial1 hdactrial2

Issues and Future of Differentiation-based Therapy

In the review by Filemon Dela Cruz and Igor Matushansky(1), the authors suggest that, like days of old of cytotoxic monotherapy, differentiation therapy would not evolve as a simplistic one-size-fits –all but mirror an extremely complicated process.  Therefore they suggest three theoretical mechanisms in which differentiation therapy may occur:

  1. Cancer directed differentiation: differentiation pathways are activated without correcting the underlying oncogenic mechanisms which produced the initial differentiation block
  2. Cancer reverted differentiation: correction of the underlying oncogenic mechanism results in restoration of endogenous differentiation pathways
  3. Cancer diverted differentiation: cancer cell is redirected to an earlier stage of differentiation

Finally the authors suggest that “the potential for reversion of the malignant cancer phenotype to a more benign, or at the very least a lower grade of biological aggressiveness, may serve as a critical clinical and biologic transition of a uniformly fatal cancer into one more amenable to management or to treatment using conventional therapeutic approaches.”

References:

1.            Cruz, F. D., and Matushansky, I. (2012) Oncotarget 3, 559-567

2.            Riester, M., Stephan-Otto Attolini, C., Downey, R. J., Singer, S., and Michor, F. (2010) PLoS computational biology 6, e1000777

3.            Seidel, C., Schnekenburger, M., Dicato, M., and Diederich, M. (2012) Genes & nutrition 7, 357-367

4.            Knipstein, J., and Gore, L. (2011) Expert opinion on investigational drugs 20, 1455-1467

5.            Marks, P. A. (2007) Oncogene 26, 1351-1356

6.            Munster, P. N., Troso-Sandoval, T., Rosen, N., Rifkind, R., Marks, P. A., and Richon, V. M. (2001) Cancer research 61, 8492-8497

7.            Napoli, J. L. (1999) Biochim Biophys Acta 1440, 139-162

8.            Moon, R., Metha, R., and Rao, K. (1994) Retinoids and cancer in experimental animals. in The Retinoids: Biology, Chemistry, and Medicine (Sporn, M., Roberts, A., and Goodman, D. eds.), 2 Ed., Raven Press, New York. pp 573-596

9.            De Luca, L. M. (1991) Faseb J 5, 2924-2933

10.          Gudas, L. J. (1992) Cell Growth Differ 3, 655-662

11.          Degos, L., and Parkinson, D. (1995) Retinoids in Oncology, Springer-Verlag, Berlin

12.          Lotan, R. (1996) Faseb J 10, 1031-1039

13.          Zhang, D., Holmes, W. F., Wu, S., Soprano, D. R., and Soprano, K. J. (2000) J Cell Physiol 185, 1-20

14.          Fontana, J. A., and Rishi, A. K. (2002) Leukemia 16, 463-472

15.          Suda, D., Schwartz, J., and Shklar, G. (1986) Carcinogenesis 7, 711-715

16.          Ciaccio, M., Valenza, M., Tesoriere, L., Bongiorno, A., Albiero, R., and Livrea, M. A. (1993) Arch Biochem Biophys 302, 103-108

17.          Palacios, A., Piergiacomi, V. A., and Catala, A. (1996) Mol Cell Biochem 154, 77-82

18.          Barber, T., Borras, E., Torres, L., Garcia, C., Cabezuelo, F., Lloret, A., Pallardo, F. V., and Vina, J. R. (2000) Free Radic Biol Med 29, 1-7

19.          Borras, E., Zaragoza, R., Morante, M., Garcia, C., Gimeno, A., Lopez-Rodas, G., Barber, T., Miralles, V. J., Vina, J. R., and Torres, L. (2003) Eur J Biochem 270, 1493-1501

20.          Omenn, G. S., Goodman, G. E., Thornquist, M. D., Balmes, J., Cullen, M. R., Glass, A., Keogh, J. P., Meyskens, F. L., Jr., Valanis, B., Williams, J. H., Jr., Barnhart, S., Cherniack, M. G., Brodkin, C. A., and Hammar, S. (1996) J Natl Cancer Inst 88, 1550-1559

21.          Murata, M., and Kawanishi, S. (2000) J Biol Chem 275, 2003-2008

22.          Schwartz, J. L. (1996) J Nutr 126, 1221S-1227S

23.          Chambon, P. (1996) Faseb J 10, 940-954

24.          Freemantle, S. J., Kerley, J. S., Olsen, S. L., Gross, R. H., and Spinella, M. J. (2002) Oncogene 21, 2880-2889

25.          Collins, S. J., Robertson, K. A., and Mueller, L. (1990) Mol Cell Biol 10, 2154-2163

26.          Grunt, T. W., Somay, C., Oeller, H., Dittrich, E., and Dittrich, C. (1992) J Cell Sci 103 ( Pt 2), 501-509

27.          Lasnitzki, I. (1955) Br J Cancer 9, 434-441

28.          Moore, T. (1965) Proc Nutr Soc 24, 129-135

29.          Saffiotti, U., Montesano, R., Sellakumar, A. R., and Borg, S. A. (1967) Cancer 20, 857-864

30.          Strickland, S., and Mahdavi, V. (1978) Cell 15, 393-403

31.          Breitman, T. R., Selonick, S. E., and Collins, S. J. (1980) Proc Natl Acad Sci U S A 77, 2936-2940

32.          Breitman, T. R., Collins, S. J., and Keene, B. R. (1981) Blood 57, 1000-1004

33.          Niles, R. M. (2000) Nutrition 16, 573-576

34.          Monagham, B., and Schmitt, F. (1932) J Biol Chem 96, 387-395

35.          Miller, W. H., Jr. (1998) Cancer 83, 1471-1482

36.          Miyauchi, J. (1999) Leuk Lymphoma 33, 267-280

37.          Reynolds, C. P. (2000) Curr Oncol Rep 2, 511-518

38.          Ortiz, M. A., Bayon, Y., Lopez-Hernandez, F. J., and Piedrafita, F. J. (2002) Drug Resist Updat 5, 162-175

39.          Mansure, J. J., Nassim, R., and Kassouf, W. (2009) Cancer biology & therapy 8, 6-15

40.          Osawa, E., Nakajima, A., Wada, K., Ishimine, S., Fujisawa, N., Kawamori, T., Matsuhashi, N., Kadowaki, T., Ochiai, M., Sekihara, H., and Nakagama, H. (2003) Gastroenterology 124, 361-367

41.          Stoll, B. A. (2002) Eur J Cancer Prev 11, 319-325

42.          Smith, M. R., and Kantoff, P. W. (2002) Investigational new drugs 20, 195-200

43.          Rumi, M. A., Ishihara, S., Kazumori, H., Kadowaki, Y., and Kinoshita, Y. (2004) Current medicinal chemistry. Anti-cancer agents 4, 465-477

44.          Papi, A., Guarnieri, T., Storci, G., Santini, D., Ceccarelli, C., Taffurelli, M., De Carolis, S., Avenia, N., Sanguinetti, A., Sidoni, A., Orlandi, M., and Bonafe, M. (2012) Cell death and differentiation 19, 1208-1219

Other research papers on Cancer and Cancer Therapeutics were published on this Scientific Web site as follows:

Histone Deacetylase Inhibitors Induce Epithelial-to-Mesenchymal Transition in Prostate Cancer Cells

PIK3CA mutation in Colorectal Cancer may serve as a Predictive Molecular Biomarker for adjuvant Aspirin therapy

Nanotechnology Tackles Brain Cancer

Response to Multiple Cancer Drugs through Regulation of TGF-β Receptor Signaling: a MED12 Control

Personalized medicine-based cure for cancer might not be far away

GSK for Personalized Medicine using Cancer Drugs needs Alacris systems biology model to determine the in silico effect of the inhibitor in its “virtual clinical trial”

Lung Cancer (NSCLC), drug administration and nanotechnology

Non-small Cell Lung Cancer drugs – where does the Future lie?

Cancer Innovations from across the Web

arrayMap: Genomic Feature Mining of Cancer Entities of Copy Number Abnormalities (CNAs) Data

How mobile elements in “Junk” DNA promote cancer. Part 1: Transposon-mediated tumorigenesis.

Cancer Genomics – Leading the Way by Cancer Genomics Program at UC Santa Cruz

Closing the gap towards real-time, imaging-guided treatment of cancer patients.

Closing the gap towards real-time, imaging-guided treatment of cancer patients.

mRNA interference with cancer expression

Search Results for ‘cancer’ on this web site

Cancer Genomics – Leading the Way by Cancer Genomics Program at UC Santa Cruz

Closing the gap towards real-time, imaging-guided treatment of cancer patients.

Lipid Profile, Saturated Fats, Raman Spectrosopy, Cancer Cytology

mRNA interference with cancer expression

Pancreatic cancer genomes: Axon guidance pathway genes – aberrations revealed

Biomarker tool development for Early Diagnosis of Pancreatic Cancer: Van Andel Institute and Emory University

Is the Warburg Effect the cause or the effect of cancer: A 21st Century View?

Crucial role of Nitric Oxide in Cancer

Targeting Glucose Deprived Network Along with Targeted Cancer Therapy Can be a Possible Method of Treatment

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