Showing posts with label taxol. Show all posts
Showing posts with label taxol. Show all posts

Tuesday, April 30, 2013


The reading about mechanisms of resistance of to Taxol calls for a new strategy for treatment of triple negative breast cancer; while it is true that PARP inhibitor should still be considered in BRCA positive cancers, adding AURORA inhibitors seems to offer logically the best opportunity to increase the activity of proposed first line drugs.

Indeed, triple negative breast cancer assumes that the receptors to conventional stimulants of the breast cancer cell are not functional or responsive.  Therefore, increasing the role of a direct attack of either the nuclear material or the microfilament/microtubule.  Taxol - Cisplatin combination achieves that!  Adding Avastin and other receptor stimulators could be a riskier proposition if you assume a questionable sensitivity of receptor in general.  Your best bet is an action on the Histones and further DNA destruction.  The cell division is your focus here and this is re-emphasized by the importance of CDKs as described by MD Anderson researchers.  As a matter of fact, the AURORA inhibitors by binding to Adenine and to the Histone appear to offer a potential and logical choice to recruit in first line to boost response rates!  So, pending proof of concept, we support the idea of adding Aurora inhibitors to a Taxane-Cisplatin core combination. Some of the Aurora Kinase also target CDKs and JAK2.  These will be my choice for new trials!

After the cancer has seen chemotherapy, endothelial cells have been altered, hypoxia has been triggered by closure of some of the blood vessel closure, the MTOR has been stimulated, we believe adding the MTOR makes more sense.  This has been also suggested after failure of Avastin,  These concepts have been publicized, It is time to move to clinical trial! (FOR THOSE WHO CAN, WE HAVE OUR HANDS TIED BY HUMAN HISTORY!)

Saturday, March 9, 2013


The other day we were in a conference discussing a case of Liposarcoma.  The man was in his 50ies and had been referred to the University surgeon for an extensive abdominal Liposarcoma that needed further resection. The disease had been resected at least twice by the community surgeon before, it had returned with significant peritoneal and pelvic infiltration.  Interval between resections had been in years, but now it was in months.  Clearly, the disease has packed further gene abnormalities now that it is evidently metastatic.  Let me take this back, because despite the widespread invasion in the abdomen, there was no tissue invasion.  There were no clear liver, lung or brain invasion.  This disease was killing a man before our eyes because of clear infiltration of abdominal tissues.
Because of the interval between surgeries, the Oncologist argued that this is a low grade tumor and may not be handled with standard chemotherapy and I strongly believe he was right.  My case with Angiosarcoma did not budge with Gemzar, Taxol followed by MAID,  I am trying AVASTIN ALONE now!
But returning to the case, the hospital and the surgery department are now breathing on the neck of the surgeon because they do not see the point of putting the patient through very expensive surgeries followed by  costly ICU stays every few months. I guess there are potential liabilities linked to the exercise. Particularly because the surgeries were done when this patient was with evident big progression of disease, but asymptomatic still.   Oncologist and Surgeon alike argued we should not wait for symptoms, because it could be inoperable by then, and an aggressive surgery plan is helpful in these local diseases.
With standard chemotherapy out the only thing left is Target therapy as an effective option.  We did not get help from the pathology department since no genetic abnormality testing is done (this is not Mayo or Harvard.  DR KRIS who speaks of gene panels in lung cancer does not live here).  And Votrient, the only  FDA approved drug is indicated in those who failed chemotherapy.  Basically, you have to put this man on chemotherapy that you know will harm him unnecessarily in order to get to Votrient (Pazopanib), an anti-VEGFR(s), Anti-c-KIT, anti-PDGFR a/Beta.  with 3-4 months advantage over placebo.


For Immediate Release: April 26, 2012
Media Inquiries: Erica Jefferson, 301-796-4988,
Consumer Inquiries: 888-INFO-FDA
FDA approves Votrient for advanced soft tissue sarcoma
The U.S. Food and Drug Administration today approved Votrient (pazopanib) to treat patients with advanced soft tissue sarcoma who have previously received chemotherapy. Soft tissue sarcoma is a cancer that begins in the muscle, fat, fibrous tissue, and other tissues.
Votrient is a pill that works by interfering with angiogenesis, the growth of new blood vessels needed for solid tumors to grow and survive.
A rare cancer with many subtypes, soft tissue sarcoma occurs in about 10,000 cases annually in the United States. More than 20 subtypes of sarcoma were included in the clinical trial leading to approval of Votrient. The drug is not approved for patients with adipocytic soft tissue sarcoma and gastrointestinal stromal tumors.
“Soft tissue sarcomas are a diverse group of tumors and the approval of Votrient for this general class of tumors is the first in decades,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Drug development for sarcomas has been especially challenging because of the limited number of patients and multiple subtypes of sarcomas.”
The safety and effectiveness of Votrient was evaluated in a single clinical study in 369 patients with advanced soft tissue sarcoma who had received prior chemotherapy. Patients were randomly selected to receive Votrient or a placebo. The study was designed to measure the length of time a patient lived without the cancer progressing (progression-free survival). The disease did not progress for a median of 4.6 months for patients receiving Votrient, compared with 1.6 months for those receiving the placebo.
The most common side effects in Votrient-treated patients were fatigue, diarrhea, nausea, weight loss, high blood pressure, decreased appetite, vomiting, tumor and muscle pain, hair color changes, headache, a distorted sense of taste, shortness of breath, and skin discoloration.
Votrient carries a boxed warning alerting patients and health care professionals to the potential risk of liver damage (hepatotoxicity), which can be fatal. Patients should be monitored for liver function and treatment should be discontinued if liver function declines.
Votrient was granted an orphan drug status designation for this indication. An orphan designation is given to a drug intended to treat a disease affecting fewer than 200,000 patients in the United States. Votrient was first approved in October 2009 for the treatment of advanced kidney cancer.

Votrient is marketed by GlaxoSmithKline of Research Triangle Park, N.C.
For more information:
FDA: Office of Hematology and Oncology Products
FDA: Approved Drugs: Questions and Answers
The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.
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For the sake of argument
1. In this man we know it is a Liposarcoma
therefore the primary deficiency is in the handling of lipid.  Insulin Receptor, may be?  IGFR, IGFBP, PPR1. CCR11

Sunday, November 25, 2012


At CRBCM we believe that CPRIT is our necessary path to Victory over Cancer.
We also know we will not get its help this time around, not because we do not deserve the help but frankly because it is distracted.  Science is an objective thing.  It is a race.  You have the right move, the right stuff, you win, no matter where you come from.  It is the Olympics without steroids.

We at CRBCM have understood one thing, in the race for the cure, harnessing the force and laws of nature has an unparalleled advantage.  Forcing a cell to die can be done by telling and convincing it to die. Or blasting it and crossing our fingers and hoping it will die.  Chemotherapy did this mostly the second way but its success was partial.  Chemotherapy only works when it manages to finally talk the language.  Indeed, some chemotherapy manages to reach the syllables of the cellular language of death.

Sorting through the maze of messages, 2 powerful set of syllables come out:

1.  That if it fails to repair broken DNA and therefore does not perform GENE REPAIR, this fact will automatically activate your P53 leading to an automatic stop of the cell into its cycle division.  There is no loophole to this principle unless the P53 is abnormal.   Knowing this is powerful.  Now we understand why Cisplatin (and to some extent Gemcitabine)  is a powerful drug because it disrupts the DNA structure.  We also understand that cells with rapid repair of DNA, will brush it off, literally.

2.with further proof of principle, we believe that there is a second automatic message or syllables.
Destruction of Microfilaments (and therefore secondarily Microtubules in general) during cell division, leads to an automatic release of Caspase from the Mitochondria no matter what (and this is what includes the BCL-2 protection). It is in this law that resides the strength of Taxanes.  Medication that works even in resistant diseases such as Melanoma where Abraxane has a role.  Taxanes' limitations appear to be in the type of microtubules attacked. Medication that attacks Microfilament of the type involved in cell divison, where the Centromere is attached, appears to send a more determinant trigger to Caspase release.  This is where our interest comes in the Anti-kinesin.  We believe and predict that an effective anti-kinesin drug in combination with Taxane and Cisplatin/gemzar based combination, will harness best this law.  They will prove to be effective in cure because they will be effective in both treatment and maintenance settings.  This is also why the combination of Gemzar and Taxol has proven to be the strongest non platinum combination.

Following this principle, we believe now at CRBCM, that target therapy not following the laws of nature will have only 20-30% response rate, meaning effective in only the cells that lack loophole mechanisms.  (this also means because of phenotype heterogeneity, 70-85% of cells have potentially intrinsic loophole to any signal transduction target stimulation or blockage).

Lets keep our eyes on the ball, do not invest in stuff they are throwing at you!  More to come...