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Cancer Diagnostics by Genomic Sequencing: ‘No’ to Sequencing Patient’s DNA, ‘No’ to Sequencing Patient’s Tumor, ‘Yes’ to focus on Gene Mutation Aberration & Analysis of Gene Abnormalities

How to Tailor Cancer Therapy to the particular Genetics of a patient’s Cancer

THIS IS A SERIES OF FOUR POINTS OF VIEW IN SUPPORT OF the Paradigm Shift in Human Genomics

‘No’ to Sequencing Patient’s DNA, ‘No’ to Sequencing Patient’s Tumor, ‘Yes’ to focus on Gene Mutation Aberration & Analysis of Gene Abnormalities

PRESENTED in the following FOUR PARTS. Recommended to be read in its entirety for completeness and arrival to the End Point of Present and Future Frontier of Research in Genomics

Part 1:

Research Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine

Part 2:

LEADERS in the Competitive Space of Genome Sequencing of Genetic Mutations for Therapeutic Drug Selection in Cancer Personalized Treatment

https://pharmaceuticalintelligence.com/2013/01/13/leaders-in-genome-sequencing-of-genetic-mutations-for-therapeutic-drug-selection-in-cancer-personalized-treatment-part-2/

Part 3:

Personalized Medicine: An Institute Profile – Coriell Institute for Medical Research

https://pharmaceuticalintelligence.com/2013/01/13/personalized-medicine-an-institute-profile-coriell-institute-for-medical-research-part-3/

Part 4:

The Consumer Market for Personal DNA Sequencing

https://pharmaceuticalintelligence.com/2013/01/13/consumer-market-for-personal-dna-sequencing-part-4/

 

• ‘No’ to Sequencing Patient’s DNA, ‘No’ to Sequencing Patient’s Tumor, ‘Yes’ to focus on Gene Mutation Aberration & Analysis of Gene Abnormalities

• Sequencing DNA from individual cells vs “humans as a whole.” Sequencing DNA from individual cells is changing the way that researchers think of humans as a whole.

• Promising Research Directions By Watson, 1/10/2013

• Disruption of Cancer Metabolism targeted by Metabolic Gatekeeper

• Molecular Analysis of the different Stages of  Cancer Progression for Targeting Therapy

First:

Predictive Biomarkers and Personalized Medicine

No to Sequencing Patient’s DNA, No to Sequencing Patient’s Tumor, Yes to focus on Gene Mutation Aberration & Analysis of Gene Abnormalities

 

MD Anderson Research

targeted agents matched with tumor molecular aberrations.

Molecular analysis

Patients whose tumors had an aberration were treated with matched targeted therapy, compared with those of consecutive patients who were not treated with matched targeted therapy

Results

40.2% – 1 or more aberration.

In 1 aberration , matched tx higher response rate  27% vs 5%

Longer time ot treatment failure  TTF 5.2 vs. 2.2

Longer survival  13.4 vs. 9 months

Pt. w/1 mutation (molecular aberrationMatched targeted therapy associated with longer TTF vs. prior systemic therapy 5.2 vs. 3.1

matched therapy was an independent factor predicting response superior to TTF

Conclusion

Not randomized study, and patients had diverse tumor types and a median of 5 prior therapies,  results suggest that identifying specific molecular abnormalities and choosing therapy based on these abnormalities is relevant in phase I clinical trials

Clin Cancer Res. 2012 Nov 15;18(22):6373-83. doi: 10.1158/1078-0432.CCR-12-1627. Epub 2012 Sep 10.

Personalized medicine in a phase I clinical trials program: the MD Anderson Cancer Center initiative.

Tsimberidou AM, Iskander NG, Hong DS, Wheler JJ, Falchook GS, Fu S, Piha-Paul S, Naing A, Janku F, Luthra R, Ye Y, Wen S, Berry D, Kurzrock R.

Source

Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. atsimber@mdanderson.org

http://www.ncbi.nlm.nih.gov/pubmed?term=22966018

 

Opinion by Dr. Pierluigi Scalia, 1/11/2013.

The fact of using nanotechnology in order to target and treat abnormal cancer cells and tissues adds a powerful weapon towards eradicating the disease in the foreseeable future. However, focusing on weapons when we still have not found a reliable way to build that personalized “shooting target” (Cancer Fingerprinting) still constitutes, in my opinion, the single most relevant barrier to the adoption of Personalized treatments.

https://pharmaceuticalintelligence.com/2013/01/09/nanotechnology-personalized-medicine-and-dna-sequencing/

Ritu Saxena’s interview

https://pharmaceuticalintelligence.com/2013/01/07/personalized-medicine-gearing-up-to-tackle-cancer/

Other studies supporting this perspective

 

p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias

 

Chromosome aberrations in solid tumors

 

Chromosome aberrations in B-cell chronic lymphocytic leukemia: reassessment based on molecular cytogenetic analysis

 

Multivariate analysis of prognostic factors in CLL: clinical stage, IGVH gene mutational status, and loss or mutation of the p53 gene are independent prognostic factors

 

Clonal analysis of delayed karyotypic abnormalities and gene mutations in radiation-induced genetic instability.

 

Comprehensive genetic characterization of CLL: a study on 506 cases analysed with chromosome banding analysis, interphase FISH, IgVH status and …

 

Detection of aberrations of the p53 alleles and the gene transcript in human tumor cell lines by single-strand conformation polymorphism analysis

 

Genetic aberrations detected by comparative genomic hybridization are associated with clinical outcome in renal cell carcinoma

 

VH mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia

 

Microarray gene expression profiling of B-cell chronic lymphocytic leukemia subgroups defined by genomic aberrations and VH mutation status

 

… nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations

 

Transformation of follicular lymphoma to diffuse large cell lymphoma is associated with a heterogeneous set of DNA copy number and gene expression alterations

[DOC] Pax 6 Gene Research and the Pancreas

 

Molecular analysis of the cyclin-dependent kinase inhibitor gene p27/Kip1 in human malignancies

Molecular genetic analysis of oligodendroglial tumors shows preferential allelic deletions on 19q and 1p.

Cytogenetic analysis of soft tissue sarcomas: recurrent chromosome abnormalities in malignant peripheral nerve sheath tumors (MPNST)

Radiation-induced genomic instability: delayed cytogenetic aberrations and apoptosis in primary human bone marrow cells

SOURCES

Search:

Gene Mutation Aberration & Analysis of Gene Abnormalities

http://scholar.google.com/scholar?start=20&q=Gene+Mutation+Aberration+%26+Analysis+of+Gene+Abnormalities&hl=en&as_sdt=0,22&as_vis=1

Second:

Sequencing DNA from individual cells vs “humans as a whole.”

Sequencing DNA from individual cells is changing the way that researchers think of humans as a whole.

The ability to sequence single cells meant that researchers could take another approach. Working with a team at the Chinese sequencing powerhouse BGI, Auton sequenced nearly 200 sperm cells and was able to estimate the recombination rate for the man who had donated them. The work is not yet published, but Auton says that the group found an average of 24.5 recombination events per sperm cell, which is in line with estimates from indirect experiments2. Stephen Quake, a bioengineer at Stanford University in California, has performed similar experiments in 100 sperm cells and identified several places in the genome in which recombination is more likely to occur. The location of these recombination ‘hotspots’ could help population biologists to map the position of genetic variants associated with disease.

Quake also sequenced half a dozen of those 100 sperm in greater depth, and was able to determine the rate at which new mutations arise: about 30 mutations per billion bases per generation3, which is slightly higher than what others have found. “It’s basically the population biology of a sperm sample,” Quake says, and it will allow researchers to study meiosis and recombination in greater detail.

SOURCES:

http://www.nature.com/news/genomics-the-single-life-1.11710#/genome

Nature 491, 27–29 (01 November 2012) doi:10.1038/491027a

https://pharmaceuticalintelligence.com/2012/11/05/every-sperm-is-sacred-sequencing-dna-from-individual-cells-vs-humans-as-a-whole/

 

Third:

Promising Research Directions By Watson, 1/10/2013

The main reason drugs that target genetic glitches are not cures is that cancer cells have a work-around. If one biochemical pathway to growth and proliferation is blocked by a drug — the cancer cells activate a different, equally effective pathway.

Watson advocates a different approach: targeting features that all cancer cells, especially those in metastatic cancers, have in common.

A protein in cells called Myc. It controls more than 1,000 other molecules inside cells, including many involved in cancer. Studies suggest that turning off Myc causes cancer cells to self-destruct in a process called apoptosis.

cancer biologist Hans-Guido Wendel of Sloan-Kettering. “Blocking production of Myc is an interesting line of investigation. I think there’s promise in that.”

Personalized medicine” that targets a patient’s specific cancer-causing mutation

Watson wrote, may be “the inherently conservative nature of today’s cancer research establishments.”

https://pharmaceuticalintelligence.com/2013/01/09/the-cancer-establishments-examined-by-james-watson-co-discover-of-dna-wcrick-41953/

 

Opinion by Dr. Stephen Willliams, 1/11/2013

Kudos to both Watson and Weinstein for stating we really need to delve into tumor biology to determine functional pathways (like metabolism) which are a common feature of the malignant state ( also see my posting on differentiation therapy).

https://pharmaceuticalintelligence.com/2013/01/09/the-cancer-establishments-examined-by-james-watson-co-discover-of-dna-wcrick-41953/

https://pharmaceuticalintelligence.com/2013/01/03/differentiation-therapy-epigenetics-tackles-solid-tumors/

Fourth:

Disruption of Cancer Metabolism targeted by Metabolic Gatekeeper

Figure’s SOURCE:

Figure brought to my attention by Dr. Tilda Barlyia, 1/10/2013

http://blogs.nature.com/spoonful/2012/12/metabolic-gatekeeper-provides-new-target-for-disrupting-cancer-metabolism.html

Author: Yevgeniy Grigoryev

In the 1920s, the German physiologist Otto Warburgproposed that cancer cells generate energy in ways that are distinct from normal cells. Healthy cells mainly metabolize sugar via respiration in the mitochondria, switching only to glycolysis in the cytoplasm when oxygen levels are low. In contrast, cancer cells rely on glycolysis all the time, even under oxygen-rich scenarios. This shift in how energy is produced—the so-called ‘Warburg effect’, as the observation came to be known—is now recognized as a primary driver of tumor formation, but a mechanistic explanation for the phenomenon has remained elusive.

Now, researchers have implicated a chromatin regulator known as SIRT6 as a key mediator of the switch to glycolysis in cancer cells, a finding that could lead to new therapeutic modalities. “This work is very significant for the cancer field,” says Andrei Seluanov, a cancer biologist at the University of Rochester in New York State who studies SIRT6 but was not involved in the latest study. “It establishes the role ofSIRT6 as a tumor suppressor and shows that SIRT6 loss leads to tumor formation in mice and humans.”

SIRT6 encodes one of seven mammalian proteins called sirtuins, a group of histone deacetylases that play a role in regulating metabolism, lifespan and aging. SIRT1—which is activated by resveratrol, a molecule found in the skin of red grapes—is perhaps the best known sirtuin, but several of the others are now the focus of active investigation as therapeutic targets for a range of conditions, from metabolic syndrome tocancer. Just last month, for example, a paper in Nature Medicine demonstrated that SIRT6 plays an important role in heart disease.

Six years ago, a team led by Raul Mostoslavsky, a molecular biologist at the Massachusetts General Hospital Cancer Center in Boston, first showed that SIRT6 protects mice from DNA damage and had anti-aging properties. In 2010, the same team established SIRT6 as a critical regulator of glycolysis. Now,reporting today in Cell, Mostoslavsky and his colleagues have shown that SIRT6 function is lost in cancer cells—thus, definitively establishing SIRT6 as a potent tumor suppressor.

In the latest study, the researchers showed that mouse embryonic cells genetically engineered to lackSIRT6 proliferated much faster than normal cells, growing from 5,000 cells to 200,000 cells in three days. In contrast, SIRT6-expressiong cells grew at less than half that rate over the same time period. When injected into adult mice, these SIRT6-deficient cells also rapidly formed tumors, but this tumor growth was reversed when the scientists put SIRT6 back into the cells.

“Our study provides a proof-of-concept that inhibiting glycolysis in SIRT6-deficient cells and tumors could provide a potential therapeutic approach to combat cancer,” says Mostoslavsky. “Additionally, SIRT6 may be a valuable prognostic biomarker for cancer detection.”

Currently, there are no approved anti-glycolytic drugs against cancer. However, the latest findings indicate that pharmacologically elevating SIRT6 levels might help keep tumor growth at bay. And there’s preliminary data to suggest that the work will translate from the bench to the clinic: looking at a range of cancers from human patients, Mostoslavsky’s team showed that the higher the level of SIRT6 the better the prognosis and the longer the survival times.

SOURCE:

Fifth:

Molecular Analysis of the different Stages of  Cancer Progression: The Example of Breast Cancer 

Figure’s SOURCE:

The molecular pathology of breast cancer progression

Alessandro Bombonati1 and Dennis C Sgroi1,2* Journal of Pathology, J Pathol 2011; 223: 307–317

(wileyonlinelibrary.com) DOI: 10.1002/path.2808

http://onlinelibrary.wiley.com/store/10.1002/path.2808/asset/2808_ftp.pdf;jsessionid=26C2C424E6948A5FAF3CBADBA385184A.d02t04v=1&t=hi26qzd4&s=a8a4aadb3fc6d448080c0ef3c67415b8277145aa

Post by Dr. Tilda Barlyia and Comments on   “The Molecular Pathology of Breast Cancer Progression”

https://pharmaceuticalintelligence.com/2013/01/10/the-molecular-pathology-of-breast-cancer-progression/

Conclusion

• No to Sequencing Patient’s DNA, No to Sequencing Patient’s Tumor, Yes to focus on Gene Mutation Aberration & Analysis of Gene Abnormalities
• Sequencing DNA from individual cells vs “humans as a whole.” Sequencing DNA from individual cells is changing the way that researchers think of humans as a whole.

• Promising Research Directions By Watson, 1/10/2013

• Disruption of Cancer Metabolism targeted by Metabolic Gatekeeper

• Molecular Analysis of the different Stages of  Cancer Progression for Targeting Therapy