Author & Curator: Aviva Lev-Ari, PhD, RN
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
Part 3:
Personalized Medicine: An Institute Profile – Coriell Institute for Medical Research
Part 4:
The Consumer Market for Personal DNA Sequencing
Part 1:
Research Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine
In Part 1, we will address the following FIVE DIRECTIONS in Genomics Research
- ‘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.
Ritu Saxena’s interview
https://pharmaceuticalintelligence.com/2013/01/07/personalized-medicine-gearing-up-to-tackle-cancer/
Other studies supporting this perspective
Chromosome aberrations in solid tumors
[DOC] Pax 6 Gene Research and the Pancreas
Molecular analysis of the cyclin-dependent kinase inhibitor gene p27/Kip1 in human malignancies
SOURCES
Search:
Gene Mutation Aberration & Analysis of Gene Abnormalities
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
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.”
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).
Fourth:
Disruption of Cancer Metabolism targeted by Metabolic Gatekeeper
Figure’s SOURCE:
Figure brought to my attention by Dr. Tilda Barlyia, 1/10/2013
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
Post by Dr. Tilda Barlyia and Comments on “The Molecular Pathology of Breast Cancer Progression”
Conclusion
The Paradigm Shift in Human Genomics will follow the following FIVE DIRECTIONS:
- 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
[…] « Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine – Par… […]
[…] https://pharmaceuticalintelligence.com/2013/01/13/paradigm-shift-in-human-genomics-predictive-biomark… […]
[…] https://pharmaceuticalintelligence.com/2013/01/13/paradigm-shift-in-human-genomics-predictive-biomark… […]
I particularly like 3 & 4, but the need to bring the genomics in alignment with a whole body of knowledge that has accrued. The whole issue that is ignored is what we have learned from 60,000 years of evolutionary biology and biochemistry.
Here’s the recap:
Predictive Biomarkers and Personalized Medicine
1. MD Anderson match to mutational aberration
Longer time ot treatment failure TTF 5.2 vs. 2.2
Longer survival 13.4 vs. 9 months
Tyrany of p! not clinical acceptable.
Tsimberidou AM, et al. Clin Cancer Res. 2012 Nov 15;18(22):6373-83. doi: 10.1158/1078-0432.CCR-12-1627. Epub 2012 Sep 10.
2. Pierluigi Scalia, 1/11/2013
build that personalized “shooting target” (Cancer Fingerprinting)
https://pharmaceuticalintelligence.com/2013/01/09/nanotechnology-personalized-medicine-and-dna-sequencing/
3. Ritu Saxena
https://pharmaceuticalintelligence.com/2013/01/07/personalized-medicine-gearing-up-to-tackle-cancer/
p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias
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
Detection of aberrations of the p53 alleles and the gene transcript in human tumor cell lines by single-strand conformation polymorphism analysis
Sequencing DNA from individual cells vs “humans as a whole.”
recombination ‘hotspots’ could help population biologists to map the position of genetic variants associated with disease.
Tough sell. This relies on information only from sperm cell.
Postgenomic events have no play.
Promising Research Directions By Watson, 1/10/2013
targeting features that all cancer cells, especially those in metastatic cancers, have in common.
turning off Myc causes cancer cells to self-destruct in a process called apoptosis
The importance of this is.. the cell has only two choices—
[1] apoptosis
[2] uncontrolled adaptive proliferation
2a. sequence of steps from minimally invasive to invasive
2b. invasion requires breaking through the cell-adhesion, which is probably related to cells piling up
2c. invasion related to actin cytoskeleton changes
Raises the question of resistance: metabolic changes promite mutation changes and
CANCER CACHEXIA is ensured when the needs of the tumor eat up the lean body mass (autocannabolization)
Disruption of Cancer Metabolism targeted by Metabolic Gatekeeper
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.
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.. “It establishes the role of SIRT6 as a tumor suppressor and shows that SIRT6 loss leads to tumor formation in mice and humans.”
SIRT6 protects mice from DNA damage and had anti-aging properties
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.
inhibiting glycolysis in SIRT6-deficient cells and tumors could provide a potential therapeutic approach to combat cancer
Additionally, SIRT6 may be a valuable prognostic biomarker for cancer detection
Molecular Analysis of the different Stages of Cancer Progression: The Example of Breast Cancer
I am still waiting for a different level of evaluation of the elements identified in Part 1.
If you ignore Part 2, we do no justice to the role translation medicine plays in Science today.
If you and Dr. Scalia do not conceptualise the following THEN the job I asked for remain UNDONE:
To put together FIVE Components in Part 1 took an intellectual effort to see the Assembly in front of one’s eyes – this is an original “gestalt” to appreciate that requires fiber far beyond the ability to write on each component alone.
To sequence Part 1,2,3,4 took an intellectual effort of synthesis few dare going there!!
You and Dr. Scalia need to bring on board each, only, a bucket on FRESHLY mixed cement to use it artfully to cement the building blogs into a structure.
Second Phase, only after, the two of you have done 1,2,3,4,5,6, below
THEN
would be, for each of YOU, to build an ALTERNATIVE structure each, at same level of analysis, as Part 1,2,3,4, for exposing the role of the human genome is/will be playing in Medicine.
Then, only then, by having Three structures – will our venture be able to claim
We are Experts, Authors, Writers at the frontier of Life Science vs. the community of bench researchers making Frontiers. We contribute to Science by proposing novel interpretation to their tedious work.
Without, us making contributions at the Synthesis level of the scientific discovery process, progress on the level of understanding for the purpose of advancement of the scientific state of affairs is left incomplete, in the hands of no one to handle the immanent Synthesis needed, for the next generation to lip forward.
What I left for you and D. Scalia to do is:
1. Part 1. Requires an integration
2. Part 1 & 2 Requires an integration
3. Part 3 Requires integration with Part 1
4. Part 3 Requires integration with Part 2
5. Part 4 Requires integration with Part 1
6. Part 4 Requires integration with Part 3
Thank You
[…] https://pharmaceuticalintelligence.com/2013/01/13/paradigm-shift-in-human-genomics-predictive-biomark… […]
[…] Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine – Par… (pharmaceuticalintelligence.com) […]
[…] Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine – Part 1 […]
[…] The Initiation and Growth of Molecular Biology and Genomics, Part I […]
[…] and Personalized Medicine – Part 1 (pharmaceuticalintelligence.com) A Lev-Ari https://pharmaceuticalintelligence.com/2013/01/13/paradigm-shift-in-human-genomics-predictive-biomarkers-and… LEADERS in Genome Sequencing of Genetic Mutations for Therapeutic Drug Selection in Cancer […]
[…] Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine – Part 1 […]
[…] Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine – Part 1 (pharmaceuticalintelligence.com) A Lev-Ari https://pharmaceuticalintelligence.com/2013/01/13/paradigm-shift-in-human-genomics-predictive-biomarkers-and… […]
[…] Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine – Part 1 (pharmaceuticalintelligence.com) A Lev-Ari https://pharmaceuticalintelligence.com/2013/01/13/paradigm-shift-in-human-genomics-predictive-biomark… […]
[…] Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine – Part 1 (pharmaceuticalintelligence.com) A Lev-Ari https://pharmaceuticalintelligence.com/2013/01/13/paradigm-shift-in-human-genomics-predictive-biomark… […]
[…] https://pharmaceuticalintelligence.com/2013/01/13/paradigm-shift-in-human-genomics-predictive-biomark… […]
[…] Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine – Part 1 […]
[…] https://pharmaceuticalintelligence.com/2013/01/13/paradigm-shift-in-human-genomics-predictive-biomark… […]
[…] https://pharmaceuticalintelligence.com/2013/01/13/paradigm-shift-in-human-genomics-predictive-biomark… […]
[…] Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine – Part 1 […]
[…] Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine – Part 1 […]
[…] Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine – Part 1 […]
[…] Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine – Part 1 […]
[…] Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine – Part 1 […]
[…] https://pharmaceuticalintelligence.com/2013/01/13/paradigm-shift-in-human-genomics-predictive-biomark… […]
[…] https://pharmaceuticalintelligence.com/2013/01/13/paradigm-shift-in-human-genomics-predictive-biomark… […]