Monday, December 17, 2012

STRATEGIES FOR THE CURE

Since the work of Weinberg and Hanahan, we know that despite the varieties of cancer, 6 driving forces lead to cancer cell survival. The "Hallmarks of cancer" result from:

1.Self sufficiency in growth signals: Cancer cells escape Anoikis, They secrete their own growth factors to achieve an autocrine stimulation.

2.Insensitivity to anti-growth signals. This is achieved by changing membranes' receptors composition and number, boosting its own global growth, and secreting Tumor Necrosis factors to tamper with surrounding cell machinery.

3.Sustained Angiogenesis, to maintain "feeding" of the new tumor mass. This is mostly critical for solid tumors. It is critical in tumors that bleed easily such as renal cell cancers.

4.Limitless replicative potential. By removing stops to mass formation, natural boundary sensors which contribute to shaping organs, Telomerase activation again.

5. Suppressing or escaping Apoptosis: By using cyclins and Bcl-2 and related molecules. Shielding Mitochondria and avoiding FAS/BAX, activating loopholes routes and impairing ubiquitination of growth molecules!

6.Tissue invasion and metastasis. Here the tumor cells alter composition, nature and amount of the cell receptors and adhsions molecules, cluster of differentiation (CD), and produce Tumor growth factors (TGF) which give it growth advantage vis-a-vis the surrounding tissue.

This list is by no mean exhaustive given the variety of possible oncogene mutations. However, when one gene is causing one of the 6 pathways, it is dubbed a DRIVER mutation for that cancer, and may have significant therapeutic importance.

This 6 venues are made of important molecular structures that can be a Target for therapy. Researcher are combing them one by one and targeting them. The successful experience with Multikinase therapy suggest that interrupting several points of the cascade appears beneficial. Computer models are being developed to see if sequential attacks or coordinated combinations would be better models for future therapies. The CRBCM is working to develop such a model. Our model will be complete after we enumerate all laws of nature (see our related series).

Model of cures should embrace these 6 venues in a mathematical equation...the challenge is launched!

sCD163 and sTARC are disease response biomarkers for Hodgkin Lymphoma

sCD163 and sTARC are disease response biomarkers for Hodgkin lymphoma

As published in Clinical Cancer Research, combined sCD163 and sTARC are better markers of disease response in patients with Hodgkin Lymphoma undergoing first-line therapy than either marker alone. sCD163 reflected tumor burden during treatment, while sTARC was more significant upon completion of therapy.

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The US Food and Drug Administration (FDA) has approved the expanded use of abiraterone acetate
( Zytiga, Janssen Biotech Inc) to first-line therapy for metastatic castration-resistant prostate cancer (mCRPC).
The drug, which decreases testosterone production, was approved in April 2011 as a second-line treatment after Docetaxel chemotherapy in the same population.
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PET/CT Agent Identifies Aggressive Renal Cancers Noninvasively
Screening patients with renal masses with iodine-124-girentuximab had both a high specificity and sensitivity for identifying clear cell renal cell carcinoma, according to the results of a newly published open-label multicenter study.

(FROM CANCER NET)

Sunday, December 16, 2012

WE ARE ENTERING THE 4TH AND LAST WEEK IN HOUSTON.
THERE IS A SENSE OF ACCOMPLISHMENT. ONE MORE TIME WE HAVE STARTED A PROJECT AND LED IT TO THE END. LIFE IS FULL OF SMALL LITTLE STEPS, ONE LEADING TO THE NEXT IN CASCADE AND PERFECT SEQUENCE. IT WILL LEAD TO WHAT IT MAY. HOPEFULLY TO A BETTER LIFE AT CRBCM! MERRY CHRISTMAS TO ALL!

Visionaries required - urgently!

For cure to happen with the CPRIT intervention, someone must have an idea or a vision based on science of what it could possibly look like. Otherwise we will be advancing in all kinds of directions. There will be sound research activities without a soul. It is the vision of what the cure will most likely look like that will help prioritize the type of projects to be funded and decide steps to be taken to achieve that objective.
If what I said is true. Then the CRBCM will call Todd Ackerman to attention. As an investigative journalist he needed to ask a follow-up question to DR Margaret Kripke, the new Chief Scientific Officer at CPRIT.
Todd asked :
"There seems to be friction between MD Anderson and the University of Texas South Western Medical Center at Dallas, the 2 institutions that have so far received most money from CPRIT. Are you, the second consecutive Chief Scientific Officer to be closely aligned with one of those institutions, concerned about real or perceived bias?"

Dr Kripke answered:
"It's certainly a concern (given) my long history with MD Anderson, I am sure there'll be a perception of some conflict of interest on my part. I hope to be able to dispel that. Under the peer review process that I hope to rebuild, I would have nothing to do with the prioritization of grants or the review of grants."

This raises a question: " WE CAN UNDERSTAND WHY THE REVIEW OF GRANTS SHOULD BE FREE OF INFLUENCE, BUT WHO THEN WILL PRIORITIZE THEM SO THAT FUNDED RESEARCH PROJECTS CAN LEAD TO THE CURE?" WHO IS IN CHARGE OF THE VISION FOR THE CURE? WE MISS THAT AS A FOLLOW-UP QUESTION, MR ACKERMAN!

THIS MIGHT OPEN THE DOOR ONE MORE TIME TO VULTURES AND HYENAS IF THERE IS NO COMPASS SHOWING THE WAY!

Cronyism not only infects cancer agency, it's spreading

By Patricia Kilday Hart

December 15, 2012

Cathy Bonner should have been thrilled when the Cancer Prevention and Research Institute of Texas opened its doors. A cancer survivor herself, Bonner had spearheaded the campaign to persuade the Texas Legislature - and Texas voters - to commit $3 billion in publicly backed bonds to find a cure for cancer. The Austin businesswoman's two parents succumbed to the disease; it also claimed her dear friend and former employer, the late Gov. Ann Richards.
"When Ann died, I'd just had it with cancer," said Bonner. "I had this concept that we could do what California did for stem cell research" by committing bonds for scientific studies. It was not an easy sell in fiscally conservative Texas, but the politically astute Bonner outmaneuvered her opponents in the 2007 legislative session. Voters signed off on the idea the same year.

But the elation of her political triumph quickly gave way to foreboding. "I disagreed when they decided we had to get private money to supplement Dr. Gilman's salary," she said, referring to Alfred Gilman, the Nobel laureate who served as the cancer agency's first scientific officer. "I knew that was going to be problematic."
After all, if Gilman knew his salary was coming from private sources, whom did he consider his boss? The taxpayers of Texas, or the foundations, pharmaceutical companies and private philanthropist who contributed to the CPRIT Foundation, which supplemented his remuneration?
Tapping private dollars
For the past six months, we've been treated to a steady stream of stories questioning the oversight of grant awards at what should have been what Bonner calls "the center of the universe" in the fight against cancer. First, Gilman resigned in protest of a $20 million award that bypassed a carefully established scientific review process; it was later revealed that an $11 million grant was awarded to a Dallas firm in which one of Gov. Rick Perry's political donors had invested without review by appropriate agency committees.
Despite careful efforts by the Legislature, the agency has become infected with the dreaded and deadly Big C: cronyism, the cancer that snuffs out trust in government.
And one carrier appears to be the CPRIT Foundation, established to tap private dollars to supplement the public agency. Dallas philanthropist Peter O'Donnell, who has generously contributed to the University of Texas and to CPRIT, at one time invested in Peloton Therapeutics, which was awarded an $11 million grant without normal review.
Oversight hindered
As CPRIT Foundation spokesman Marc Palazzo told the Chronicle's Eric Berger and Todd Ackerman last week, private foundations proliferate throughout state government. As he put it, "It has long been public knowledge that a portion of those funds has been used to supplement the salaries of senior executives at CPRIT. This practice is modeled after those used by multiple other Texas state entities."
Palazzo is right: Private foundations exist throughout state government. And in many cases, their existence shields state officials from public scrutiny.
Last week, the New York Times reported that Texas leads the nation is granting tax breaks as an economic development tool. The newspaper noted that Perry frequently takes corporate recruitment trips underwritten by a nonprofit known as TexasOne, which is financed by large corporations and consultants, including politically active Dallas tax consultant Brint Ryan.
According to the Times, Perry's office approved "enterprise zone" awards worth millions of dollars every year to 222 companies between March 2008 and June 2012. Of those, 82 were clients of Ryan's tax consulting firm.
Fun fact: Both TexasOne and the CPRIT Foundation are managed by Austin public affairs consultant Jennifer Stevens.
A private foundation also loomed large in a scandal that rocked the UT School of Law last year.
Dean Larry Sager was asked to resign after it became known he had obtained a $500,000 "forgivable loan" from the school's private foundation, which he never disclosed to UT's administration. He also obtained foundation money to provide salary supplements for favored professors, creating deep disparities in compensation among the faculty.
Legal blessing
Now, the state auditor, the Travis County District Attorney's Office, and the Texas Attorney General's Office are conducting investigations into the cancer institute and its foundation.
Several embattled cancer institute officials have resigned, creating an opportunity for the cancer institute to make a fresh start. A former M.D. Anderson administrator, Margaret Kripke, was named chief scientific officer.
Would her salary be supplemented by the private foundation, as Gilman's was?
"Under the law creating the Cancer Prevention and Research Institute, the agency may supplement the salary of the executive director and other senior institute staff members. Funding for a salary supplement may come from gifts, grants, donations or appropriations. CPRIT's chief scientific officer does receive a supplement to the base salary," CPRIT spokeswoman Ellen Read wrote in an email.
I'll take that as a yes.

CPRIT, A CHALLENGE FOR THE CRBCM

HOW CAN YOU TELL THE TRUTH TO SOMEONE IN CHARGE OF FEEDING YOU. HOW CAN YOU TELL THE TRUTH TO AN ORGANIZATION THAT CAN CHANGE YOUR LIFE.
The CRBCM was in a CONUNDRUM. We had a choice to make, denounce what was going on at CPRIT in order to free it from an inevitable shrinking of its potentials, or stay quiet and play it safe to keep our chances intact for obtaining a grant now or in the future. Events at CPRIT however forced the hands of the CRBCM. CPRIT under intense scrutiny, dropped its approval of grants from 20-25% to 11% this round. Restricting its allocations of grants strictly to universities and Biotech companies. There we knew strains on CPRIT had taken its toll. We understood that current leaders at CPRIT were not being bold and risk takers. Our chances to have a grant is "zero" under the current leadership. We had to denounce the situation. As a Coalition, we have to fight these unfriendly environments at CPRIT.

By choosing to invest in Universities and Biotech, CPRIT is living in the future. The time it will take to form companies, to discover new cellular pathways, find a product, put it in a clinical trial and passing FDA approval. we are talking 5-10 years at least. CPRIT has 7 years left to be. The cure in 10 years still has a chance, but most likely after the current CPRIT. And life of contemporary Texans will not significantly change. We need to create Jobs now and expand the foot print of CPRIT. Injecting more money into MD Anderson is a safe investment in the mind of the public. But how many more jobs do you expect them to create? I really doubt they will add to their work force the same number of jobs like a new company in El Paso could! Are they more likely to find a cure? May be, but don't be so sure! The search for the cure is a race. If you are serious about finding it without politics, give a chance to more people to compete! Create true competition. It may keep them on their toes and eventually help them!

The notion that reviewers should come from out of state is being sold to us as a strong proof of impartiality. It sounds "safe". But it means ignoring realities on the ground in Texas. That El Paso needs jobs may not be a factor for out-of-state Reviewers. Is this what the CPRIT founders clearly intended? Then, the NCI needs to bring in foreign reviewers for its process to be impartial. But clearly the NCI doesn't! CPRIT needs a reform of its culture... We should be ashamed that we do not believe in ourselves anymore. How did we end up like this!(I am trying to get a reaction, if you get my drift!). El Paso women had to starve and camp before the White House to call for jobs before this last Thanksgiving!

CPRIT has chosen to grow from out of State in, and not from In state out. Don't you think a balanced approach may be better since no approach is free of "side effects"? Middle ground is good! " Easy come, Easy go" remember!

ALL WE MEAN AT CRBCM IS GOOD FOR CPRIT, DON'T KILL US FOR BEING A COALITION THAT FIGHTS FOR ITS CAUSE. WE WOULD NOT BE A COALITION WITHOUT STANDING UP TO BE COUNTED! AND CPRIT WILL NOT BE THE CPRIT WITHOUT CLEARING ITS NAME!
FOR THE RECORD WE PARTICIPATED IN "NEW DIRECTIONS AT CPRIT". We are going for an appeal. Let's God help us!

Saturday, December 15, 2012

TELOMERASES

ONCE AGAIN NATURE PLAYS IT SIMPLE FOR BIG THINGS!
ONE OF THE WAY NATURE CHECKS THE AGE OF CELLS IS BY CHECKING THE LENGTH OF THEIR DNA SKIRT ATTACHED AT THE END OF THEIR CHROMOSOME. ALL CELLS OF SAME TYPE START WITH A RELATIVELY SAME LENGTH OF SKIRT. WITH ANY DIVISION, THE SKIRT IS CUT SHORTER. IF THE SKIRT IS TOO SHORT TO EXPOSE THE END OF THE CHROMOSOME, THE CELL HAS LIVED LONG ENOUGH AND IT IS SENT FOR DESTRUCTION. THE LENGTH OF THE SKIRT CAN BE PROLONGED BY SOME ENZYMES THOUGH TO FOOL THE CHECK SYSTEM. THESE ENZYME ARE CALLED THE TELOMERASES.

CANCER CELLS DO NOT DIE BECAUSE THEY ACTIVATE THEIR TEL-O-MERASE. AND EACH TIME THEY DIVIDE, THEIR TELOMERASE RESTORE THE LENGTH OR JUST GIVE THEM THE LONGEST SKIRT EVER TO BEAT THE SYSTEM! RESEARCHERS ARE WORKING HARD TO SILENCE THE CANCER CELL TELOMERASES! THE CRBCM IS LOOKING INTO THIS!

AT A CHECK POINT IN CELL DIVISION 2 MAIN THINGS HAPPEN:

1. DNA is checked for mistakes and corrections are undertaken.2. Chromosome segregation to eventual daughter cells is checked to avoid uneven distribution of the chromosome.
This last event seems to rely heavily on activity on unattached chinetochores where check point proteins (MAS 1 & 2, UB1 etc.) accumulate and block the APX (Anaphase promoting complex) until the checking is completed and Cyclin B and Securins are ubiquitinated and destroyed to release the check hold and allow mitosis to proceed.

The need for ubiquitination of Cyclin B elevate the role of Proteasome. That is why Antiproteasome appears very important in hematologic conditions where signal transduction and subsequent cyclin activity are the driving forces toward multiplictaion of cancer cells as we stated.

When all this is going on, the cancer cell is at its weak point. That is why chemotherapy, particularly the Taxanes and the Vinca-alkaloids, is more effective. It not only disturbs the microtubule (inducing the 2nd law), but also breaks the actinic anchors to the cytoskeleton of membranes and cellular matrix causing the "Anoikis" like phenomenon within the cell. Lesion to actin like molecules (anchors) within the central nervous system could lead to neuropathy. As we know it has the side effect of these drugs (proof of concept to follow).

Ponatinib in CML

FDA Approves Ponatinib for Rare Leukemias

Zosia Chustecka

Disclosures Dec 14, 2012

Editors' Recommendations

Drug & Reference Information

Ponatinib ( Iclusig, Araid) was approved today by the US Food and Drug Administration (FDA) for use in patients with 2 leukemias that have stopped responding to other therapies, and offers new hope for these subgroups of patients. The approval comes 2 months earlier than expected.
Ponatinib is approved for use in patients with chronic myeloid leukemia (CML) and also Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (Ph+ ALL) who have relapsed or are refractory to other therapies. Many of these patients, but not all, have developed a T3151 mutation, which makes the disease resistant to the standard treatment with tyrosine kinase inhibitors (TKIs) such as imatinib ( Gleevec).
"The approval of ponatinib is important because it provides a treatment option to patients with CML who are not responding to other drugs, particularly those with the T3151 mutation who have few therapeutic options," said Richard Pazdur, MD,

CPRIT MAY LOSE NCI SEAL OF APPROVAL!

The NCI announced that federal officials are looking into events at CPRIT. It is unclear whether their evaluation will only lead to recommendations about the NCI seal of approval status, or whether they are searching for federal crimes at CPRIT. Our fear for CPRIT's future is that a broader investigation will expose more irregularities in grant allocations, and that more people will be charged with criminal misconducts. Voters were right to vote for CPRIT funding. Cancer needs to be met at higher intensity. What voters did not predict was that CPRIT will end up being taken over by "evil people" or "vultures and hyenas" in the words of a renowned Nobel Laureate who worked there. What needs to occur at CPRIT is a complete purge which should change leardership and culture at CPRIT. CRBCM would like to be invited to the conversation about the future of CPRIT. We believe that broader measures and safeguards need to be implemented to not only preclude failures in grant allocations, but also to make sure CPRIT is more inclusive and responsive to minority concerns. CPRIT has funded mainly Universities and Biotech companies in a race where even underdogs should be allowed to come up with the right ideas and should be given a chance! CRBCM is such an underdog! It is interesting to note that the departing chief executive wants to stay on until the next round of grant allocation. The CRBCM is worried that his participation will be detrimental to our cause since we voiced our opinion. It also will be ground for our next appeal. Let it be known!

FLIPPASE, FLOPPASE, SCRAMBLASE

One of nature's secret and ability to hide it, is by being simple. While we expect things to be complicated and full of contorsions, we are startled when at the end what we find is simple to understand! One of the things we had figured out to be simple is the role of flippase and floppase, and may be the role of scramblase. If one looks at a battery we use to power small electric equipment, one side is positive, the other is negative. So there is a positive pole and a negative pole. We can conclude that the battery is polarized. The limit of a cell or one way the cell keeps what is inside of it, is by having its membrane polarized like an electrical fence. The cell has understood that to be electrically polarized you got to have molecules in the membranes full of electrons. And these electron-filled-molecules need to be maintained in position no matter what ! So the cell figures we need some Flippases and floppases to put things in the order above. Meaning if the molecules we need in position A is outside the cell in position B, flip it in the right position A no matter what. While flippase go A to B bringing these molecule inside. Floppase goes B to A, sending molecule outside. The Scramblase does both functions to mix things up!

This seems simple enough but wait!
This is how the cell tells the other cell "I am a dead cell, get rid of me"
Indeed, dead cells move Phosphatidyl serine, a normally internal surface molecule, to the outside of the cell, making it one of the most powerful signals to the Macrophage that this cell needs to be attacked and removed.
This disruption in lipid molecules is also linked to Bleb formation in the membrane, another powerful sign of cell death. It is related to Caspase activity as an inducer of death, and therefore it is related to our 2nd law of nature which induces Caspases. YOU CAN SEE HOW SIMPLE THINGS GET COMPLICATED FAST! (This is also linked to protein Kinase activation, by the way!)
QUESTION NOW: ARE FLIPPASE AND SCRAMBLASE TARGET FOR THERAPY? You better believe it.

We are working hard at CRBCM, but CPRIT is resisting with the help! Please help us!

NOTE A is inside the cell
B is outside the Cell, in our example.

Friday, December 14, 2012

The cofilin pathway in breast cancer invasion and metastasis

Weigang Wang , Robert Eddy & John Condeelis

Recent evidence indicates that metastatic capacity is an inherent feature of breast tumors and not a rare, late acquired event. This has led to new models of metastasis. The interpretation of expression-profiling data in the context of these new models has identified the cofilin pathway as a major determinant of metastasis. Recent studies indicate that the overall activity of the cofilin pathway, and not that of any single gene within the pathway, determines the invasive and metastatic phenotype of tumor cells. These results predict that inhibitors directed at the output of the cofilin pathway will have therapeutic benefit in combating metastasis.

One of the ways to achieve this is ANOIKIS (detachment induced cell death). Cells within a tissue are destined to live together. And any cell that becomes undone, will trigger more likely the 2nd law of nature through its cytoskeleton alteration and enter Apoptosis or programmed cell death. It appears that the cancer cell prepares its departure by changing its membrane receptor composition, altering its cytoskeleton and undergo numerous changes before embarking in the metastatic process. The Cofilin system described above by scientists is linked to the activity of ACTIN, a major component of the Cytoskeleton. It is suspected that the entire cell has a nerve system made of Actin based complex which makes the microfilament. This is why our 2nd law is so powerful. Destabilization of the microfilament apparatus in the cell will beak loose all things attached to cell membrane (including Cytochrome C, the activator of caspases but also cause detachment of organelles attached to sarcoplasmic or reticulum membranes). Again, the second law is so powerful because it is caused basically by Actin change or break. Attacking Actin for the cell is like attacking the skeletal and nervous system of the human being. At the Nuclear level, attacking Actin seems to activate Endonucleases which in turn will break the DNA and trigger the first law. We are still working at the CRBCM to ascertain some of the proofs of principle mentioned here!

and another grant application sent out this minute...

...this sure was a very busy and brain wrecking time to get those grant applications out in time. There is always the last minute e-bug or hang-up that occurs with the online application forms , but we are getting better with each application: a total of 6 research projects have been submitted for funding since May 2012!

1. Intervention and research through flowcytometry and cytogenetic studies of basal cell type breast cancer in African American women and ways to reverse mortality

2. Comprehensive and staged program to promote a healthy lifestyle:"Focus on diet, weight control and exercise as a way to decrease cancer risk in El Paso, TX"

3. Comprehensive Breast Cancer Prevention and Mortality Reduction Program

4. Comprehensive Health Intervention Program to Reverse Breast Cancer Mortality in El Paso, Texas

5. Early Detection of Lung Cancer through levels of e-Cadherin,Metallopeptidase, Tumor Growth Factor Beta,presence of MDM2 mutation & correlation with PET findings

6. Grass-Roots Outreach program to help 10,000 women in El Paso with Breast Cancer education, awareness, screening and overall healthier lifestyle

CRBCM has submitted a new Application for research as promised.
we keep working hard and El Paso is waiting to go to work. It is not that we are not trying to
represent El Paso. It is that we just don't have the clout of Houston, Dallas and Austin. El Paso still does not have the political weight of Dallas. But this will not stop us from trying.
There is a thing about perseverance, sometimes it pays!

We are completing our 3rd week in Houston, will leave Houston December 22nd. Just in time to celebrate Christmas in El Paso, land of the Miners. Slated to cover the hospital while in town. So continuing to work hard until it pays! Look forward to a meeting with another Oncology Clinic Doc 28. We plan to combine efforts!

Thursday, December 13, 2012

Attended Mark G Kris lecture on Lung Cancer (KRIS IS FROM MSKCC)

Now genetic sequencing is important

Prescribe the following

1) EGFR-------------ERLOTINIB, GEFITINIB
2) ALK-----------------CRIZOTINIB
3) HER-2--------------HERCEPTIN, LAPATINIB
4) BRAF -------------------VEMURAFENIB
5) ROS-1-----------------CRIZOTINIB (AGAIN)
6) RET--------------------------VANDETANIB (CABOZANTINIB)
7)MET------------------------CRIZOTINIB (AGAIN)

NICE THE PRESCRIPTION SPELLING OUT ONLY THE GENE SEQUENCING, AND LET YOUR PHARMACIST DO THE REST.
QUESTION: COULD THESE DRIVER GENE ABNORMALITIES BE THE SAME IN TRIPLE NEGATIVE BREAST CANCER?

Wednesday, December 12, 2012

Bill Gimson, Executive Director Of Cancer Prevention and Research Institute of Texas, Asks To Resign

By PAUL J. WEBER 12/11/12 06:41 PM ET EST

AUSTIN, Texas — Turmoil surrounding an unprecedented $3 billion cancer-fighting effort in Texas worsened Tuesday when its executive director offered his resignation and the state's chief public corruption prosecutor announced an investigation into the beleaguered agency.
No specific criminal allegations are driving the latest probe into the Cancer Prevention and Research Institute of Texas, said Gregg Cox, director of the Travis County district attorney's public integrity unit. But his influential office opened a case only weeks after the embattled agency disclosed that an $11 million grant to a private company bypassed review.
That award is the latest trouble in a tumultuous year for CPRIT, which controls the nation's second-largest pot of cancer research dollars. Amid the mounting problems, the agency announced Tuesday that Executive Director Bill Gimson had submitted his letter of resignation.
"Unfortunately, I have also been placed in a situation where I feel I can no longer be effective," Gimson wrote in a letter dated Monday.
Gimson said the troubles have resulted in "wasted efforts expended in low value activities" at the agency, instead of a focused fight against cancer. Gimson offered to stay on until January, and the agency's board must still approve his request to step down.
His departure would complete a remarkable house-cleaning at CPRIT in a span of just eight months. It began in May, when Dr. Alfred Gilman resigned as chief science officer in protest over a different grant that the Nobel laureate wanted approved by a panel of scientists. He warned it would be "the bomb that destroys CPRIT."
Gilman was followed by Chief Commercialization Officer Jerry Cobbs, whose resignation in November came after an internal audit showed Cobbs included an $11 million proposal in a funding slate without a required outside review of the project's merits. The lucrative grant was given to Dallas-based Peloton Therapeutics, a biomedical startup.
Gimson chalked up Peloton's award to an honest mistake and has said that, to his knowledge, no one associated with CPRIT stood to benefit financially from the company receiving the taxpayer funds. That hasn't satisfied some members of the agency's governing board, who called last week for more assurances that no one personally profited.
Cox said he has been following the agency's problems and his office received a number of concerned phone calls. His department in Austin is charged with prosecuting crimes related to government officials; his most famous cases include winning a conviction against former U.S. House Majority Leader Tom DeLay in 2010 on money laundering charges.

"We have to gather the facts and figure what, if any, crime occurred so that (the investigation) can be focused more," Cox said.
Gimson's resignation letter was dated the same day the Texas attorney general's office also announced its investigation of the agency. Cox said his department would work cooperatively with state investigators, but he made clear the probes would be separate.
Peloton's award marks the second time this year that a lucrative taxpayer-funded grant authorized by CPRIT instigated backlash and raised questions about oversight. The first involved the $20 million grant to M.D. Anderson Cancer Center in Houston that Gilman described as a thin proposal that should have first been scrutinized by an outside panel of scientific peer-reviewers, even though none was required under the agency's rules.
Dozens of the nation's top scientists agreed. They resigned en masse from the agency's peer-review panels along with Gilman. Some accused the agency of "hucksterism" and charting a politically-driven path that was putting commercial product-development above science.
The latest shake-up at CPRIT caught Gilman's successor off-guard. Dr. Margaret Kripke, who was introduced to reporters Tuesday, acknowledged that she wasn't even sure who she would be answering to now that Gimson was stepping down. She said that although she wasn't with the agency when her predecessor announced his resignation, she was aware of the concerns and allegations.
"I don't think people would resign frivolously, so there must be some substance to those concerns," Kripke said.
Kripke also acknowledged the challenge of restocking the peer-review panels after the agency's credibility was so publicly smeared by some of the country's top scientists. She said she took the job because she felt the agency's mission and potential was too important to lose.
Only the National Institutes of Health doles out more cancer research dollars than CPRIT, which has awarded more than $700 million so far.
Gov. Rick Perry told reporters in Houston on Tuesday that he wasn't previously aware of the resignation but said Gimson's decision to step down was his own.
Joining the mounting criticism of CPRIT is the woman credited with brainstorming the idea for the agency in the first place. Cathy Bonner, who served under former Texas Gov. Ann Richards, teamed with cancer survivor Lance Armstrong in selling Texas voters in 2007 on a constitutional amendment to create an unprecedented state-run effort to finance a war on disease.
Now Bonner says politics have sullied an agency that she said was built to fund research, not subsidize private companies.
"There appears to be a cover-up going on," Bonner said.
Peloton has declined comment about its award and has referred questions to CPRIT. The agency has said the company wasn't aware that its application was never scrutinized by an outside panel, as required under agency rules.
___
Follow Paul J. Weber on Twitter: www.twitter.com/pauljweber

Great Read: ASCO’s Blueprint for Transforming Clinical and Translational Cancer Research

"Accelerating Progress Against Cancer"
http://www.asco.org/ASCOv2/Department%20Content/Cancer%20Policy%20and%20Clinical%20Affairs/Downloads/Blueprint.pdf

There is also an online tutorial about how to better plan and conduct Translational Research and conclude with a high-impact paper to publish.

Tuesday, December 11, 2012

CPRIT CHIEF EXECUTIVE WILLIAM GIMSON HAS RESIGNED HIS POSITION.
He heard the voice of reason. Those close to him thanked him for his efforts.
"Men pass, institution remains". It is time to not double down on wrong policies. It is time to broaden the views at CPRIT. With the new scientific review chief officer, let CPRIT broaden its wings and rise to its full potential. We here at CRBCM will stop any commentary negative about CPRIT, let it soar to achieve the cure we all want.

CPRIT/BIOALLIANCE

The number of participants to a recent CPRIT RFA (Request for Application) is unknown to the CRBCM. But according to a recent published participation in a CPRIT meeting, up to 800 applications could have been received. All applicants had to pay one thousand dollars with their applications. for a separate commercialization review. You are free to submit more than one application as long as you pay more money. The money goes not to CPRIT, but in its wings is located Bio-Alliance. Who are they? How come they are in charge of reviewing CPRIT applications? Where is the CPRIT review crew.?
We at CRBCM had a chance to meet Dr. Larson, the Bio-Alliance commecialization reviewer in charge. He told us he had no experience with neither the medicine related to cancer, nor its prevention. He "specializes in commercialization of drugs and devices" and from what he told us, is finding Biotech companies mostly from out of state (not from Texas) to bring them to Texas. He did not tell us that until after we contacted and met him to discuss the Comprehensive project of the CRBCM which is located in El Paso. Why? to get 1000 dollars from one more applicant? The last CPRIT meeting revealed 11% chances of getting a grant. So potentially, Bioalliance stands to gain up to 1000,000 dollars from applicants. And 89% of them will lose their application money? or are people reimbursed if not successful? we doubt it?

The President of Bio-Alliance came to the meeting with us. He seemed content. I did not know why.
I soon found out: "Dr ...can't say your name, frankly speaking, I did not read your project...but can you tell me about your background...?" I knew right there, this was a joke! But I played along for respect of CPRIT. We had learned about Dr. Larson because his name was mentioned in the RFA as a person who can help. The CRBCM submitted our application draft to this man. He could have sent us an e-mail, to explain that he did only look at drug and device commercialization projects, but he called for a meeting telling us that people will be "joining us". And they came to the meeting without reading what it was about. Does this sound to you like a representative of CPRIT? But mark my words, people paid 1000 dollars to have their project reviewed. The money is going to a friend of CPRIT! Sounds like cronyism or Nepotism at CPRIT. The current management is taking CPRIT where ever they want. They have decided to fund mostly UNIVERSITIES because the public will not really object. That's bias! The fundamental crime against minorities and small private institutions. Where is the Equal Opportunity Commission on this! But look at it the other way, may be the CPRIT story was started by a University fund raising scheme! Good start for an interesting investigation! We have a lot to say to James Drew, a Dallas Journalist. He is the investigator, not me.

(This is an opinion based on facts that I came to meet through this experience with CPRIT)
The NIH needs to learn from this. The may ask 1200 dollars to be paid to CRBCM, and I promise not to read the applications! and now and then invite the applicant in my office to see them squeal ! Ask them about their background, and you get the picture!

BAD POLITICS!

Still fevereshly preparing our response.
We will speak today with James Drew from the Dallas Newspaper.
He seems inceasingly interested in CPRIT.
We will see how far he will go.
We will still talk to them until they understand that we are not planning to go away that easy. We believe we can contribute. And by principle we should not just be brushed aside. We remind ourselves that we are a Coalition for a Good Cause, we will fight Cancer, and negative politics that make the cure even more difficult to achieve than the disease itself!

Monday, December 10, 2012

Welcome to our followers in Brazil and India!
Let's all put our heads together and push the research into the Cancer cell behavior until we find the most efficient and least harmful way to catch them before they replicate and invade us all!

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Latvia	10
China 8

Two new slim slivers of expectation to do reserach with CPRIT!

It was interesting to hear the CPRIT Scientific Review Officer. At last a person. Appeal of the rejection is possible. Resubmission of our project in spring 2013 is possible, too.
Small chances, but chances is all we need!
However, this waste of time is frustrating. Cancer patients, contrary to paper tigers, do not have idle time to sit around, but need and deserve the best care and research we can give them now!

CPRIT has just agreed to us publishing their comments on our projects and grant requests. Good.

MESSAGE TO ALL LEADERS!

No matter how big you are, if you splurge in misconduct, cheating or abuse of power, you will never achieve your potential. You will lose respect and people will always know who they are dealing with.
You will survive, but over time you will become irrelevant, you will not rise in the heart of men, you will be a false hero. At the worst people will throw a shoe at you, or foment some other curse. Do not forget this as you spread your wings. Every society needs its leaders to stand for truth and justice. Even under attack, people will stand by you if they know you are a true fighter, and if you happen to fall, the living will glorify you and remember the good about you. Do not live to be forgotten or despised. Life is for leaders to make a difference. Some leaders are remembered for their wickedness. Those memories bring disdain to our souls.
Leaders who make a true difference are those who fought for justice and inclusion of masses. People are judged not only for their accomplishments, but also by how good they were as human beings. No one is perfect, so if you make a mistake, seek amend. Don't taunt people because you are powerful. Perfidy will always lead to disgrace, because if you indulge in it, it will not be long before you meet your match. The public forum is not a place to bring treason, because sooner or later, you will receive the "scorn".
Remember one thing: in the eye of observers, it is not your victims and their fate that people will judge. It is how you relish your so-called "Victories" on them that will be judged! Particularly when observers realize, it was all wrong!

Phase III Clinical Trial of Doxorubicin Alone or in Combination with TH-302 for Soft Tissue Sarcoma That Is Locally Advanced or Inoperable

This is a new study by a major university MSK trying to test a new concept whether penetrating hypoxic areas of the tumor by a new chemotherapy would make a significant difference. The study end-point is survival. This is a tall order for a study because most of them only look at disease free survival. The challenge here is that hypoxic areas may not be significant satellite or hiding place (sanctuary) for tumor cells since their own survival could be impaired by hypoxia. But in this refractory disease, a new trial testing a new concept is welcome news!

A corollary problem brought to mind, certain tissues have certain targets that are prominent. finding these targets for these tissues could be a more intelligent approach as we face some of the tough/refractory cancers. We look forward to seeing this new drug make a difference for our patients.

Sunday, December 9, 2012

GLOBAL CHALLENGES IN CANCER

As I am listening to DRS Irene Ghobrial and Paul Richardson discussing about a difficult case of refractory Myeloma, a blood cell cancer involving plasma cells, I am increasingly struck by the fact that blood cell disorders seems to respond to treatment aimed at steps in the signaling cascade starting at the membrane, deep into the cell at the nuclear level. In Myeloma, signal pathways and interaction with the stromal milieu of cancer cells, seems to be the Trend. Here our 5th law seems to predominate. Everything is added to Velcade to work. Proteasome inhibition is king. But as soon as you enter leukemia and lymphoma, we are back to the 1st and 2nd law where destruction of DNA and microtubules appears to be the current predominant approach. Whether this emphasis on attack of Signal transduction versus DNA destruction is imposed by research or driven by what works in the clinic, is clearly not sure. It could also be due to the type of abnormality happening within the cell.
The first impression is that in Myeloma, signal transduction is the major disturbance area, where in Myelodyspasia and leukemia, transcription factors (TF) (ACTIVITY OF VIDAZA/DECITABINE SUPPORTS THIS) and nuclear DNA disturbances appear to be major causal forces . In solid tumor, because of the need for mass creation, epidermal/ membranous phenomena (events and composition of receptors at the membrane) and nuclear and perinuclear (TF) events appear to be the main areas of disturbance. Signal transduction, globally secondary to membrane receptor stimulation, seem less important, although genetic heterogeneity in various individual make them more or less signal transduction interruption susceptible.

As we move forward, drugs are being develop to hit hundreds of targets in chain of reactions steps which follows a circuitry in cascade. We are plugging here while unplugging there. sometime we are applying multiple plugs at the same time (ie Muti-kinase inhibitors). Computer models will help here. What we don't know yet is whether the sequence of plugging is important to stop (full language of the cell) major escape mechanisms for the survival of cancerous cells. Already major trends are being discovered as covered by our proposed various laws. The fight is on, let's keep working.

For those who missed out on the controversy...

Texas cancer institute to re-review controversial grant

31 May 2012 | 22:45 GMT | Posted by Meredith Wadman | Category: Biology & Biotechnology, Health and medicine, Lab life

Ronald DePinho and Lynda Chin

The largest grant to date from one of the world’s major institutional funders of cancer research will be re-reviewed, officials overseeing the award now say, even as the grant’s high-profile recipients steadfastly assert the money was fairly awarded and would be well spent.
The Texas cancer world has been rocked by controversy since the 8 May resignation of Alfred Gilman, a Nobel laureate and chief scientific officer at the US$3-billion, taxpayer-funded Cancer Prevention and Research Institute of Texas (CPRIT) in Austin.
In leaving, Gilman cited his concerns about an $18-million “incubator” grant speedily awarded in March, without scientific review, to a team at the Institute for Applied Cancer Science (IACS) at MD Anderson Cancer Center in Houston.
The controversial grant’s purpose is to build infrastructure that will speed the development of cancer drugs by, among other things, expanding the small-molecule pipeline to include biologics, and boosting current target biology and small molecule discovery efforts. (Rice University in Houston, a partner with the IACS, would receive $2 million as part of the same award.)
Lynda Chin, the cancer researcher who was listed as principal investigator on the IACS team, is the IACS scientific director and is also married to MD Anderson president Ronald DePinho. The couple moved to the huge institution last August from the Dana-Farber Cancer Institute in Boston, Massachusetts. At that time the lines of authority governing Chin’s reporting, potential promotions and salary were outlined in this e-mail to her and DePinho from Kenneth Shine, the executive vice-chancellor of health affairs for the University of Texas system.
In his resignation letter, Gilman complained that the CPRIT had in March sidelined seven scientific grants that had already been reviewed and recommended and were worth $39 million. He added that he would stay on in the job for several months “to champion the research slate” and “to prevent further award of vast funds for research programs ostensibly within incubators that were not described and therefore could not have been reviewed.” A subsequent letter to the CPRIT oversight committee from its scientific-review council, headed by biologist Philip Sharp of the Massachusetts Institute of Technology, called the 6.5-page incubator proposal from Chin and colleagues “research,” even if “strikingly lacking in specific[s]”. “We are surprised and disappointed by the failure of proposals of this sort to receive scientific (research) peer review,” the committee wrote.
The CPRIT’s decision to re-review the grant emerged during a quick exchange of letters in which DePinho offered to have it vetted again and William Gimson, CPRIT executive director, agreed to take up the offer in his same-day response. However, Gimson’s letter makes clear that, as with the first review, it will be conducted by the CPRIT commercialization review council — the panel that passed muster on it the first time — and not by scientific reviewers.
DePinho and Chin both agreed to speak with Nature yesterday. Here is a condensed version of their remarks:

What is your version of what has happened that has led to the current controversy?
DePinho: Long before we arrived in Texas there was a good debate [at CPRIT] as to the balance of [spending on] research and commercialization and prevention. There were new programmes that CPRIT embarked on: incubator projects. This led to a request for applications (RFA).
Many people said to us: you really should consider applying. We were not even considering it.
The application was a business plan. It was clear they did not want the science. They assumed the science was strong. We had a very very strong track record in that regard.
The next thing that occurred was this firestorm of concern from Dr. Gilman. And I understand frankly that he went through a very rigorous process of recommending funding for [research] grants. And then priorities were set at the level of CPRIT that impacted on the ability to fund all of those grants. And they were very understandably upset.
But the reality is: we applied for an RFA, we worked with people who encouraged us to do this… It was reviewed and it got funded. The process… was done in a way that was totally consistent with CPRIT’s guidelines.
There’s a lot of concern that something nefarious was done. And I believe that’s unfounded. The facts will speak for themselves. And I am happy to have the grant re-reviewed by anybody.
Your wife is listed as the principal investigator on the $18-million incubator grant. Some in the public could perceive this to be a nice tidy deal for both of you. How do you respond?
DePinho: It’s important to note that Lynda reports to Ken Shine, the [executive vice-chancellor of health affairs] at the University of Texas system. She doesn’t report to anybody within the [MD Anderson] organization.
Second, [MD Anderson] committed $75 million over five years [to the IACS] and one of the things that it encouraged this group to do was to apply for grants to enhance their programme.
Realize that it was a team of half-a-dozen individuals, including Lynda, that submitted this grant. How Lynda ended up as the PI, I do not know.
I understand that the optics of this — that people would raise some questions… . [But] this was a grant going to an institute supported by a team acting on a mandate from the [MD Anderson] institution to secure grants.
What do you think should happen next?
DePinho: The important thing is to not throw out a baby with the bathwater; to make sure things that are worthy of funding, including those research grants that fell below the payline, get supported. At the same time, I believe that the IACS will go down as one of the best investments in the CPRIT portfolio.
The guidelines are the guidelines and we adhered to them. They can always be improved. But to characterize this as a flawed process and to cast aspersions on individuals that were doing what they were supposed to do is not helpful to anybody.
To Lynda Chin: What do you think has engendered the current controversy?
Chin: I frankly am somewhat mystified as to how this controversy arose. If you go back to the CPRIT’s RFA online, it specifically was requesting a business plan for an infrastructure to support commercialization. And the IACS is a unique entity: the best way to think of it is as a business within MD Anderson. And it’s the only entity at MD Anderson that qualified to respond to this RFA as a team.
If there was controversy over how the incubator infrastructure grants should be approved, that should have been within CPRIT. Because the RFA specified how this business plan was going to be reviewed. We as a team could only go by what the RFA said.
You said just now that IACS is a business. But you have no products or company name. How do you defend that definition?
Chin: That’s very straightforward. The business plan for the IACS was developed, reviewed and approved by the [University of Texas] system prior to our final recruitment to MD Anderson in August last year. It mandated milestones we have to meet, deliverables that include drugs that will eventually help patients, and requirements to deliver funds… . It dictates the type of people we will recruit… who will execute a work plan to generate a product — not to publish. I can tell you there’s no research lab that operates that way.
What do you say to a Texas cancer scientist who applied through standard CPRIT channels for research funding and failed to win it? Who feels, now, unfairly dealt with?
Chin: Look at the mandate of CPRIT. It was funded by taxpayers for prevention, commercialization and research… . It was built with three different review councils to address [these] three different aspects.
I do research. I understand and absolutely support the importance of basic research, because there’s so much we don’t know. And until we do, we can’t fully conquer cancer. Having said that, no single Cell, Science or Nature paper has ever cured a patient, until [it’s converted] to a drug, a test or a medical device… . To the scientists who say this is not fair, I would remind them that our goal here is to help our patients.
Your husband is in a powerful role — and some might say there’s an appearance here, fair or unfair, of money gravitating to power. How do you respond?
Chin: The business plan is for the IACS. The IACS is a team effort. This team is mandated to bring in external funding. I am only one member of that team. The funding is not something that I will use for my research programme. I have separate research programmes that require separate funding. My trainees will not benefit from this funding. This is specifically going into the institute.
What would you like to see happen next?
We believe this award of infrastructure will ultimately deliver tremendous benefit to the patients. I would like to see MD Anderson and CPRIT get to the point of negotiating a contract.

Comments

01 Jun 2012 09:48 GMT

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Ally Kanamisa said:: I would like to thank Dr Chin for her openness to respond to the questions posed by Nature . It is apparent to me that getting to the point of negotiating a contract for your hybrid “academic-industry model” requires to not bypass the rules or authority (Provost) sustaining the integrity of organizational and regulatory components of those two units( academia-industry). Remember that the main and ultimate target of this hybrid model is a human being, cancer patient, who needs a cure. And commercialization, as intended by the taxpayer, revolves and evolves around her/him.
In regard to your statement that the business plan was approved by UT before your final recruitment, my question is: do you see this award, then, as part of your start up funds?. I seem to understand from your statements that the answer is NO. It follows that your application (in response to the RFA), is in the context of a hybrid model to serve cancer patients and should contain not only a business plan but also a scientific plan. By the way, in the RFA is stated:
“Does the Applicant propose a sound program evaluation plan, including scientific review, commercial viability, milestone measures, expected deliverables, and required accomplishments? ….”
It is difficult to understand the approval of an incubator award requiring to proposed scientific review that has not being reviewed by scientific peers in the first place.
Allow me to tell you that I also feel mystified by your husband assertion: ““The application was a business plan. It was clear they did not want the science. They assumed the science was strong. We had a very very strong track record in that regard.”. It seems to me that business people and lay people may assume that the science is strong. However, we scientists are taught that “ in science you don’t take anything for granted”. That’s the expected attitude of a scientist and implies to expose oneself to the scrutiny of peers to endorse our proposals.
Dr Chin, you appear to be an incredible woman scientist. There is no reason for fear to expose your scientific ideas and plans. Please, complete your proposal and resubmit it for review. It is in your best interest and that of your credibility. And set up an example for the state of Texas, the country and the world.
Thank you and I wish you the very best
Ally
PS to Nsture: In the letter from Gimson it is stated” Incubator RFA is designed for commercial ventures and any proposal submitted must comply with that criterion”.
Commercial ventures are not to be exempted from specified and clear ethical guidelines. In particular, when commercial ventures claim to have as main, though not only, objective the treatment, cure and safety of cancer patients. There must be objective, well defined, parameters to comply with in order to ensure that the population is at minimum risk when it comes to her health and ECONOMICS. We are globally suffering the devastating consequences of a financial crisis and “there are lessons to be learned from the process” . This is a quote from correspondence between Gimson and DePinho: “These commercialization incubator awards are uncharted territory for all of us and there are lessons to be learned from the process. For example, at MD Anderson should not be reviewed by the Provost’s Office but by the Business Affairs and we are instituting this process.”
We don’t need to set up a very questionable precedent.

Saturday, December 8, 2012

To Texas Governor Rick Perry

To Texas Governor Rick Perry:

The Coalition for the Reversal of Breast Cancer Mortality in African American Women (CRBCM) would like to approach you as the leader for the Texan Community to bring your attention to the fact that current conditions at CPRIT are not allowing this organization to fully complete its mission. CPRIT is involved in a series of scandals depicted daily in Newspapers. Frankly speaking, CPRIT's future and work cannot be continued under current management without endangering its potential. CPRIT has grown nervous in deciding who gets grants. This clearly makes it less likely to invest in low income and minority benefiting programs which in the eye of the public would be considered "riskier". The bias is to pour money into the coffers of universities and Biotech companies which are perceived as safer investments. This severely compromises CPRIT foot print and the potential impact in the communities as small and minority corporations are excluded.

Despite the involvement of current management in CPRIT's birth, the CRBCM believes that the results of CPRIT will be covered with suspicions under current management. Doubt has set in, and the journalists will not let go. In fact, I truly believe that criminal investigation will soon kick in. I am not an investigator. But this mess should somewhere prompt the FBI to investigate this as there is a strong perception of cronyism, and favoritism is rampant at CPRIT. The bias for university funding and policy of favoritism to big biotech companies will soon have the Equal Opportunity Commission and Consumer Protection Agency to be involved. This mess could be stopped by your intervention to remove or suggest a change of leadership at CPRIT.

The current CPRIT management is involved not only in shady deals, but the love of secrecy. Why should a government Agency muzzle applicants to RFAs by claiming that the information they give them is privileged and can only be released to the public with CPRIT's authorization? What is there to hide unless they are afraid it will reveal the poor quality of the work done at CPRIT? As we speak, I went through the process. What I got as review of my work is not at the high level claimed to characterize the reviewers.

CPRIT's management is a sinking ship because the attitude is wrong at CPRIT. We need your leadership to weigh in and stop the drift before more money is wasted. As a Coalition, we will continue to fight because the cause is too important. We need to save lives and create jobs in El Paso.

Sincerely yours

Mutombo Kankonde, MD. MPh.
President
CRBCM

The good old CPRIT had concerns about minorities SINCE THEN IT IS ALL UNIVERSITIES!
/www.cprit.state.tx.us/images/uploads/cprit-min-03102010.pdf
THE BIAS IS FLAGRANT

5th Law of Nature...

5th LAW OF NATURE, DISABLING THE FBW7/UBIQUITINATION FOR CANCER GROWTH

FOR CANCER GROWTH, THE NATURAL TENDENCY IS FOR GROWTH OF ABNORMAL CELL. IT IS PARAMOUNT FOR THE CANCER CELL TO PARALYZE THE UBIQUITINATION OF P53. THIS WILL RESULT IN A NET INCREASE OF USED OR PHOSPHORYLATED P53
WHICH HAS SEVERAL EFFECTS:
(ASSUMPTIONS)

1. BLOCKING THE BAX WAY TO CASPASE CASCADE MOST LIKELY BY NON-UBIQUINATED CYCLIN RESIDUE BUILD UP.

2. DISABLING THE SONS OF THE SEVENLESS, ULTIMATELY PARALYZING ACTIVATED P53 LEADING TO PROGRESSION OF THE CELL CYCLE DESPITE CONCURRENT CHANGES IN DNA (FIRST LAW ESCAPE). THIS IS ACHIEVED THROUGH IN CREASE OF PHOSPHORINATED MOLECULES NOT DESTROYED THROUGH PROTEASOMES

3. INCREASE PRODUCTION OF MUTATED P53 LEADING TO INCREASE, THROUGH TRANSCRIPTION FACTORS, OF THE POOL OF ABNORMAL P53 RESIDUE OR INHIBITORY MOLECULES

4. C-MYC UPREGULATION WOULD BLOCK ARF, A BREAK OR INHIBITOR TO MDM2.

THIS IS WHY MUTATION IN THE MDM2 IS ONE OF THE MOST COMMON MUTATIONS FOUND IN CANCER BECAUSE IT DESTROYS OR SUPPRESSES THE UBIQUITIN LIGASE INVOLVING P53 TO FORCE CELLS INTO CYCLE EVEN IN THE PRESENCE OF DNA BREAKS AND / OR ERROR/MUTATION.

CANCEROUS GROWTH HAS TO PARALYZE APOPTOSIS MAINLY BY ALTERING CONCENTRATION OF NON-WILD TYPE P53.

THIS IS ALSO WHY ANTI- PROTEASOME DRUGS (SUCH AS VELCADE) ARE THE MOST POWERFUL DRUGS AFTER ANTI-MICROTUBULE DRUGS (SEE 2ND LAW). DESTRUCTION OR NEGATION OF PROTEASOME PROCESSES SEEMS TO PRESERVE MOLECULES THAT CONQUER THE BAX SUPPRESSION OF BUILD UP NON UBIQUITINATED P53.

2 OBSERVATIONS FOLLOW:

1. THIS MECHANISM IS VERY IMPORTANT IN HEMATOLOGIC CANCERS WHERE SIGNAL TRANSDUCTION ABNORMALITY IS THE DRIVING FORCE. ARSENIC TRIOXIDE WILL HAVE A SIGNIFICANT EFFECT HERE SINCE IT ATTACKS SEVERAL AREAS RANDOMLY IN THE SIGNAL TRANSDUCTION PATHWAYS. COMBINING IT TO VELCADE WILL HOWEVER BE MOST LIKELY TOO TOXIC.

2. A COMBINATION OF ABRAXANE AND VELCADE WILL BE THE MOST POWERFUL COMBINATION OF ALL COMBINATIONS (MAY BE WITH THE ADDITION OF ANTI-KINESIN) FOR TRIPLE NEGATIVE BREAST CANCER.(OR ANY CANCER).

PROOF OF PRINCIPLE:

1.CAN QUANTITATION OF PHOSPHORINATED P53 BE ACHIEVED IN PEOPLE WITH CANCER (WITH MUTATED MDM2) ?

2. SHOULD MDM2 MUTATION BE A BETTER SURROGATE FOR PRESENCE OF CANCER

3.WHAT IS THE LEVEL OF CYCLINS AND BAX ACTIVITY IN PATIENT WITH MDM2 MUTATION.

4.MDM2 MUTATION INDUCES GROWTH FACTOR PRODUCTION (ie. tgf BETA) THROUGH
INCREASE OF RELEVANT TRANSCRIPTION FACTORS, INCREASE RECEPTORS OR DIRECT EFFECT OF NON UBIQUITINATED P53.

5. STATUS OF THE SONS OF THE SEVENLESS IN MDM2 MUTATION. IS MDM2 MUTATION A PROGNOSIS FACTOR IN CANCER.

AND SO ON...

Coalition for the Reversal of Breast Cancer Mortality in African American Women