INTERESTING ARTICLES. GO TO THEM!

1.Plastin3 is a novel marker for circulating tumor cells undergoing the epithelial-mesenchymal transition and is associated with colorectal cancer prognosis

Cancer Research, 02/21/2013 

(APPARANTLY THIS IS NOT FOUND NATURALLY IN NORMAL BLOOD)

2Multicentre phase II trial of bevacizumab combined with docetaxel carboplatin for the neoadjuvant treatment of triple-negative breast cancer (KCSG BR-0905)

Annals of Oncology   02/06/2013

STUDY COMPLETED IN KOREA

WE WANT TO SEE YOU THERE

New and Improved for 2013 Interactive and educational, Great Debates and Updates in GI Malignancies will focus on controversial areas in the management of gastrointestinal malignancies as nationally-recognized thought leaders take opposing sides on topics of clinical interest. Located conveniently in New York City, discussions at Great Debates and Updates in GI Malignancies this year will include: • Clinical update and novel therapies for hepatocellular carcinoma • Genetics and GI cancers – How genetics are helping us identify, predict and decrease risk as well as determine new therapeutic targets • What is the optimal chemoradiotherapy for locally advanced, unresectable esophageal and GE junction adenocarcinomas? • Is there hope on the horizon for KRAS-mutant tumors and for BRAF-mutant tumors in the management of colorectal cancer? For more information, visit the conference website: imedex.com/gi-malignancies-debate-conference/

MORE INFORMATION REGISTRATION Early Registration Deadline March 14, 2013 Presentation Dates April 5-6, 2013 Location New York, NY Westin New York at Times Square Conference will feature ARRAY technology - bring your laptop or tablet and participate with the most up-to-date information

MICROSATELLITE INSTABILITY IN TRIPLE NEGATIVE BREAST CANCER?.

One will not think of this normally, but because of its good prognosis a biomarker, and because of its positive predictive value in terms of response to therapy, One may want to know its participation if any or share in triple negative breast cancer.
Microsatellite instability is almost standard of care a request in Colorectal cancer as it has entered the ASCO and NCCN guidelines.   But is it exclusive to COLORECTAL cancers.

' Lynch syndrome (HNPCC or Hereditary nonpolyposis colorectal cancer ) is an autosomal dominant genetic condition which has a high risk of colon cancer^[1] as well as other cancers including endometrium, ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited mutations that impair DNA mismatch repair.'

This definition clearly exclude Breast Cancer however it would be of clinic interest to test triple negative breast cancer for these features in trying to further define the various group of this condition.  Likelihood of finding anything is low. But may be we can find a cohort, a subtype that we can declare of good prognosis?

New Genetic Links to Colorectal Cancer Identified

 By Anna Azvolinsky, PhD¹ | January 2, 2013

¹Freelance Science Writer and Cancer Network Contributor. Follow Her on Twitter

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Three new genetic links to colorectal cancer have been identified using a large genome-wide study of more than 28,000 individuals. The three new variants may hold potential new therapeutic targets and are helping researchers better understand the biology of colorectal cancer as well as the differential genetic basis of colorectal cancer in European and Asian populations. The study is published in Nature Genetics.

Researchers at the Vanderbilt-Ingram Cancer Center in Nashville, and colleagues in China, South Korea, and Japan analyzed 5,252 colorectal cancer cases and 9,071 control samples from the Asia Colorectal Cancer Consortium (ACCC) to identify novel colorectal cancer risk factors. The samples studied came from China, Japan, and Korea. The results were compared to the known genetic variants identified from European population results.
“This kind of work would not be possible without the support of investigators from multiple centers,” said Wei Zheng, MD, PhD, an Ingram professor of cancer research and lead author of the study.
The top four genetic loci were compared to two previous data sets—the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and the Colon Cancer Family Registry (CCFR). Three of these were also identified in these previous European analyses, although the three loci were more strongly associated with the East Asian populations than the European population.
“A lot of work has been done in European descendants,” said Zheng. “Our study is the first one conducted in multiple East Asian populations. Looking at different ethnic groups is important because the genetic structures can be different enough that variants identified in one population do not explain risk in other populations Sometimes—it is much easier to identify some genetic variants in East Asian populations than European descendants.”
One of the loci is in close proximity to the CCND2 gene, a cyclin that has a critical role in cell cycle progression and has been shown to be overexpressed in colorectal tumors in various studies including The Cancer Genome Atlas (TCGA). Another variant is located proximal to the PITXI gene, a tumor suppressor gene that may activate TP53 and regulate the activity of the enzyme telomerase, which adds telomeres to the ends of chromosomes. A third genetic variant includes two genes—HAO1, which encodes a hydroxyacid oxidase; and PLCB1, which encodes phospholipase C-β1. PLCB1 has been previously shown to be overexpressed in colorectal cancer tissue.
Further genetic analyses of colorectal cancer continue to be necessary. Previous genome-wide studies have isolated 15 common genetic susceptibility loci in colorectal cancer but only 15% of heritable colorectal cancer is explained by these loci. All but one of these colorectal cancer studies analyzed samples from European populations even though genetic variants from non-European populations differ from those of other populations, including Asian populations.
Moreover, only 6% of colorectal cancer cases are explained by the genetic variants previously identified and associated with a high risk of the disease.
In addition to its work on colorectal cancer, the team is working on breast cancer genetics to identify additional genetic loci that confer risk of developing cancer, leading a consortium that has identified multiple susceptibility loci for breast cancer in Asians. “Interestingly,” said Zheng, “these loci were not discovered in previous studies conducted in European descendants, even with a very large sample size.”

CLINICAL RESEARCH AND COMMERCIALIZATION FOR OUR CPRIT SUBMISSION.

Our suggestion of a CPRIT submission formulated on Oct 14th (see our posts) has excited our readers
we felt compelled to dig deeper in this story.  We basically suggested that in Prostate Cancer, the incidence was much higher as opposed to a relative low mortality.  We went on to say that this paradox begs scientists to find ways of discriminating which Prostate Cancer should be considered dangerous for our patient to compel us to aggressively treat the patient.  We suggested that a cancer that is spreading needs to be treated because only metastasis ( spread of the cancer) can kill the patient.  How to tell which cancer will spread?  We submitted that cancer cells before they spread, needed to lose their attachments to other cells by decreasing their Membrane Adhesion Molecules.  One of the Adhesion Molecule of interest was E-Cadherin.  We therefore suggested that in all cancers of the prostate, dosing the amount of Adhesion molecule was a way to predict its potential for spreading.  If we make it simple to quantify E-Cadherin, a kit can be commercialized to determine quickly the spread of disease.  We also suggested that cancer cells to penetrate tissues and leading to organ failure and killing the host, must create its road through cellular tissues.  It needs to secrete enzymes called Metalloproteases (2,9) to break through.  We suggested that a high level of these Metalloproteases in the biopsy tissue could predict a moving cancer.  A Kit to detect Metalloproteases could be commercialized to help Doctors take medical decisions for the benefit of patients.  All this, if proven in our intended research could advance medical practice.

There is further discussion to have about this:

1. Could Blocking Metalloprotease gene stop the spread of disease?
2. Could restoring E-Cadherin level or function stop the spread of disease?
Scientist from California believe that  activating P120 could restore E-Cadherin function efficiently enough to restore or correct deficiency of E-cadherin function.  Should we use this approach to slow down cancer.

The story of E-Cadherin is just beginning.  We know that cancer in fact spread very early.  In small cell lung cancers, Doctors perform a bone marrow biopsy to see that even in early stage, the cancer has already invaded away from the lung.  This is true also in Breast cancer where even in stage I (the first stage of Breast cancer) the Bone marrow could already be invaded.  The meaning of this distant invasion has been interpreted with controversy.  But even in these cases, it portend a bad prognosis.  Worse prognosis then that of patient with negative Bone Marrow finding. DOES E-CADHERIN REDUCTION CORRELATES WITH POSITIVE INVASION OF THE BONE MARROW?  COULD WE SPARE PATIENTS A BONE MARROW PROCEDURE IF THE E-CADHERIN IS LOW. These are some of the question that have a bearing on clinical matter and would impact today practice as we move forward.

The level of E-Cadherin has broad implications.  In Colon cancers, particularly in the Familial Adenomatous Polyposis (FAP), The E-cadherin level could predict not only evolution to cancer state of the Polyposis but also and again predict metastasis.  He even beg to suggest that it could have prognosis implication.  The decrease of E-cadherin has profound consequence on the amount the Beta-catenin that E-cadherin can not longer "sequester".   Whether this will lead to increase the Cyclin D level down the line could be assumed and therefore sustain life of cancer cell.  It is also worth mentioning that in the sequence of gene Mutation leading to Colorectal cancer, the loss of 5q (ADENOMA PHASE)which seems to correspond to the phase where Beta- Catenin is important is the earliest stage in the sequence of transformation.  This fact correspond to the "good Prognosis" of these cancer....COULD E-CADHERIN REDUCTION BE  AN EARLY SIGN OF COLORECTAL CANCER METASTASIS?  OR SHOULD THIS MODEL BE CHALLENGED?

Assuming we find a Molecule A which, when it is incorporated by the cell, it opens up and adopt a conformational change increasing phosphorylation of Beta-Catenin leading it to proteasomic destruction, could that decrease Cyclin D formation and induce Apoptosis?  What would be the impact if that incorporation was selective to cancer cells?  These are the challenges we face!

Through genetic intervention, could we restore the wnt-signalling pathways to prevent FAP and prevent removal of the Colon in FAP? Remember this, 80-85% of sporadic colorectal cancers have disturbance in the wnt pathways, what we are talking about could impact the majority of Colorectal cncers (second leading cause of cancer death in the United States)

Does the wide spread use of Calcium based product for Osteoporosis prevention correspond to decrease of Colorectal cancer in the terminal colon.  Calcium is critical in the function of membrane receptors.

The cure is achievable, let get it!

More HYPOTHESIS FOR CANCER RESEARCH

Given what we know now, could intermittent use of Cipro and laxative (5 days every 6-8weeks) be the most effective prevention against Colorectal cancer?  The CRBCM is reviewing data to make this assumption. There is sufficient scientific data to suggest this is true and a larger clinical trial is warranted to assess this hypothesis.
Through the work of others, we now know that Ciprofloxacin has anti-topoisomerase activity.  That is comparable in its mechanism  to some powerful chemotherapy drug.   But compared to chemotherapy drugs, it has been used for longer periods safely.   It is not innocuous, nothing is, however, it has been used broadly and side effects denounced to date may all be reversible.  The major concern of such broad use of an antibiotic will be potential hematologic toxicity and bacterial resistance. This is to be balanced against prevention of a deadly disease (colorectal cancer).  Intermittent use could address some of these concerns.
Development of other safer mild anti-topoisomerase could result to avoid CIPRO use, and preserve it in our Antibiotic armamentarium.

It is now known that certain bacteria produce chemical molecules such as nitrates that affect the colonic epithelium.  And that the progression to Colon cancer is an evolutionary process, possibly this evolution to cancer cells is driven by chronic continuous irritation.  Cleaning intermittently the colon has been assumed to be good as it provides an interruption in these irritations.  It would make sense if the laxative follows the Cipro.

ADDING AN ANTI-PROSTAGLANDIN MAY HAVE ADDITIONAL EFFECT.

Given the fact that this may be controversial, it would make sense to have a broader discussion before implementing this idea. Tell me what you think!

Looking into the role of Ciprofloxacin in cancer cell apoptosis

Colorectal cancer (CRC) is the second most commonly diagnosed cancer and the second leading cause of cancer mortality in the United States among cancers that affect both men and women.
Screening lowers colorectal cancer (CRC) incidence and mortality. CRC is preventable through the removal of premalignant polyps and is curable if diagnosed early. Increased CRC screening and reduced CRC incidence and mortality are among the Healthy People 2020 objectives.
What if CRC could be prevented, at least to a certain degree?

Here an interesting finding that will need further research and require validation in the endeavor to prevent cancer, CRC being a priority target:
Pulm Pharmacol Ther. 2010 Oct;23(5):373-5. Epub 2010 Mar 6.
"Ciprofloxacin can significantly affect eukaryotic cells including human cancer cells. Its bactericidal action relay on inhibition of topoisomerase II, enzyme responsible for alterations in 3D structure of DNA during replication, transcription and chromatin condensation. Thanks to that, ciprofloxacin can induce cell cycle arrest and apoptosis of cancer cells."

The stakes are high. Lives can be saved. The cost to society for premature death from CRC are too high - we need to become even more proactive than with screening alone.
The medical and societal costs of CRC are substantial. Estimated direct medical costs for CRC care in 2010 were $14 billion, with projected costs of up to $20 billion by 2020 (13). In 2006, estimated lost productivity costs for persons who died from CRC were $15.3 billion (14). This equals $288,468 of lost productivity per CRC death in 2006 (14). Screening costs per person vary by test. The lifetime (age 50--80 years) average per person cost of screening ranges from $71 per person for guaiac-based FOBT to $1,397 per person for colonoscopy (15).