The Combination of Etoposide and Histone Deacetylases applied to Cancers with high levels of c-MYC and c-FOS gene expression

The Combination of Etoposide and Histone Deacetylases applied to Cancers with high levels of c-MYC and c-FOS gene expression:

This research project investigates the possibility of combining Etoposide with Histone Deacetylases in the treatment of cancers that display a significant expression of te c-Myc and c-Fos gene.  The drugs proposed for this trial are Etoposide and Histone Deacetylases.

Etoposide was first synthesized in 1966 and is a drug widely used in chemotherapy since 1983 when it obtained  FDA approval. Etoposide forms a ternary complex with DNA and the topoisomerase II enzyme which participates in the unwinding of DNA, hence prevents the rwligation of the DNA strands, and by doing so causes DNA strands to break. This action then  leads to DNA synthesis errors and subsequently to cell death. Etoposide has, however, some reported side effects such as low blood pressure, hair loss, pain or burning at the injection site .

Histone deacetylation has been an effective treatment for various types of cancers. By the removal of acetyl groups from histones, histone deacetylases create a non-permissive chromatin conformation that prevents the transcription of genes that regulate the expression of proteins involved in tumor development such as c-FOS. In addition to histones, histone deacetylases deacetylate a variety of other proteins including transcription factors and other abundant cellular proteins involved  in the regulation of cell growth, differentiation and cell death. Histone Deacetylases are among the most promising therapeutic targets for cancer treatment, and they have inspired researchers to study and develop HDAC inhibitors worldwide.

The present research project consists in computerized and laboratory testing of the efficacy of combining these two treatments in cases of observed overexpression of both the c-MYC and c-FOS gene.  Although the two drugs already exist and are used in cancer therapy, the interaction of  the two drugs when used in combination needs to be examined. This can be achieved by using a mouse model bearing specified tumors to be done at the University of Texas at El Paso (UTEP). Preliminary testing should be conducted by implanting cancer cells in the skin of mice. The combined treatment should then be applied indiscriminately to mice presenting high expression of c-Myc and c-FOS, and to those with low expression of these genes. The response to the treatment will be monitored to evaluate the efficacy of the treatment in mice with high c-Myc and c-FOS expression as compared to the control group with low c-Myc and low c-FOS expression. In a later phase, testing would be conducted  in cancer patients presenting high expression of c-Myc and c-FOS, especially for patients treated for triple negative breast cancer, but also for ovarian cancer and other types of cancer with an overexpression of c-MYC.

The combination of Etoposide with Histone Deacetylases represents de facto a novelty in cancer treatment, especially in the case of triple negative breast cancer that is until today associated with a worse prognosis than other breast cancer types. It has a characteristic recurrence pattern with the peak risk of recurrence and the majority of deaths occurring in the first 3 and 5 years after the initial treatment, respectively.

The secret of triple negative breast cancer

Common sense tells us that events happening in your women when they acquire childbearing age contribute significantly to the happening of triple negative breast cancer.   The young woman has gone through infancy when events here are more related to the setting of class I HLA antigens first for self tolerance, then comes exposure to the outside world and the building of defense mechanisms.  Implying development of class II HLA Antigens which we know by now are very much linked in their variations to racial disparity.  Then the young woman enters puberty which brings in the reign of the Estrogen with its extensive methylation of genes dampening the Class I HLA to prepare the young lady's body to receive the foreign "body" of the potential infant.  We have touched in one of our precedent writings about the effects of Estrogen on the immune system.   We have extensively discussed the interaction of Interferon and TNF /TGFs on receptors of Estrogen (Activation followed by desensitization or lack thereof.  The female individual with autoimmune disease will be much more affected by the surge of cytokines above.  Then come the menses with their resulting Iron deficiency which prones the body to the danger of Reactive Oxidative species.  But as far as genes are a concern, the most important event is the development of the breasts.  It is the reign of the PROLACTINS.....
Indeed, it is Prolactins that will happen on this background of Estrogen/Cytokines effects.   Don't think of Prolactin as a hormone, it is a Cytokine!  Yes, it comes in to not only have a direct effect on the Janus Kinase 2 and induce the JAK-2-STAT pathways, but through its Dopamin Receptor, it will pound on the c-MET effect and exert numerous pounding on the PIK (effect include on its regulators (AGAP2) pathway....If you happen to have another genetic abnormality such as BRCA, or too much free Iron stimulating the HIF or any other failure....something wrong is bound to happen....such as ...triple negative breast cancer.....The point is, don't forget the Prolactin reign!!!

A few questions in triple negative breast cancer

1.Could amplification of PIAS modulate enough the STAT to impact progression of triple negative Breast cancer?
2.Could modifiers of Sumoylation impact the prognosis of triple negative breast cancer?
3.Status of the Zimp10 in triple negative breast cancer?
4. Amplifying ART-27 to stop cellular proliferation?
5.blocking RCHY1 could restore P53 function in patient with non Mutated P53?
6.can anti-cortactin and supervillin block metastatic propensity of triple negative breast cancers?
watch brain mets?

TRIPLE NEGATIVE BREAST CANCER TREATMENT

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!)

TRIPLE NEGATIVE BREAST CANCER WITH BASAL CELL LIKE CANCER CELLS

Are you kidding me or just fooling me?
Could patients having this disease also have a Glycosylation problem?
Are they suffering from a form of Hereditary Multiple exostosis?
Do they have EXT gene Mutation?
 By claiming the following:
"The mechanism of HME pathology is likely rooted in a disruption of the normal distribution of HS-binding growth factors, which include FGF and morphogens such as hedgehog, Wnt, and members of the TGF-β family. The loss of HS disrupts these pathways"

Hudson Freeze et al are reporting all the mechanisms involved in Basal cell  breast cancer in one sentence and pin it down to Heparan surface.  He is putting the disruption square and round in the Golgy Apparatus.

It makes perfect sense though, these diseases are triple negative pointing to an insensitive receptor
and sure enough we know that receptors are proteins, but in order to work, proteins need Glycosylation and Heparan Sulfate is  :

"Heparan sulfate /hep·a·ran sul·fate/ (hep´ah-ran) is a glycosaminoglycan occurring in the cell membrane of most cells, consisting of a repeating disaccharide unit of glucosamine and uronic acid residues, which may be acetylated and sulfated; it accumulates in several mucopolysaccharidoses."(wikipedia)

Lack of Glycosylation will render receptor insensitive!

THIS IS THE FULL TEXT OF THEIR CLAIM:
Congenital Exostosis

Defects in the formation of heparan sulfate (HS) cause hereditary multiple exostosis (HME), an autosomal dominant disease with a prevalence of about 1:50,000. It is caused by mutations in two genes EXT1 and EXT2, which are involved in HS synthesis. HME patients have bony outgrowths, usually at the growth plates of the long bones. Normally, the growth plate contains chondrocytes in various stages of development, which are enmeshed in an ordered matrix composed of collagen-chondroitin sulfate. In HME, however, the outgrowths are often capped by disorganized cartilagenous masses with chrondrocytes in different stages of development. About 1–2% of patients also develop osteosarcoma.
HME mutations occur in EXT1 (60–70%) and EXT2 (30–40%). The proteins encoded by these genes are thought to exist as a complex in the Golgi and both are required for polymerizing GlcNAcα1–4 and GlcAβ1–3 into HS. However, the partial loss of one allele of either gene appears sufficient to cause HME. This means that haploinsufficiency decreases the amount of HS and that EXT activity is rate limiting for HS biosynthesis. This is unusual because most glycan biosynthetic enzymes are in substantial excess.
The mechanism of HME pathology is likely rooted in a disruption of the normal distribution of HS-binding growth factors, which include FGF and morphogens such as hedgehog, Wnt, and members of the TGF-β family. The loss of HS disrupts these pathways in Drosophila. Mice that are null for either Ext gene are embryonic lethal and fail to gastrulate; however, Ext heterozygous animals are viable and about one third develop a visible exostoses on the ribs. No exostoses develop on the long bones of these animals (in contrast to patients with HME), but subtle chondrocyte growth abnormalities were seen in the growth plates of these bones. Further studies are needed to understand how truncation of the HS chains leads to ectopic growth plate formation and the phenotype abnormalities.

It becomes urgent to test EXT gene in these patients the TRAP1 gene

TRAP1,
Retinoblastoma protein.^[5]

EXT1

From Wikipedia, the free encyclopedia

Jump to: navigation, search

Exostosin 1
Identifiers
Symbols	EXT1; EXT; LGCR; LGS; TRPS2; TTV
External IDs	OMIM: 608177 MGI: 894663 HomoloGene: 30957 GeneCards: EXT1 Gene
EC number	2.4.1.225 2.4.1.224, 2.4.1.225
[show]Gene Ontology
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	2131	14042
Ensembl	ENSG00000182197	ENSMUSG00000061731
UniProt	Q16394	P97464
RefSeq (mRNA)	NM_000127	NM_010162
RefSeq (protein)	NP_000118	NP_034292
Location (UCSC)	Chr 8: 118.81 – 119.12 Mb	Chr 15: 53.06 – 53.35 Mb
PubMed search	[1]	[2]

Exostosin-1 is a protein that in humans is encoded by the EXT1 gene.^[1]
This gene encodes an endoplasmic reticulum-resident type II transmembrane glycosyltransferase involved in the chain elongation step of heparan sulfate biosynthesis. Mutations in this gene cause the type I form of Multiple Exostoses.^[1]

From Wikipedia, the free encyclopedia

Jump to: navigation, search

TNF receptor-associated protein 1
Identifiers
Symbols	TRAP1; HSP 75; HSP75; HSP90L; TRAP-1
External IDs	OMIM: 606219 MGI: 1915265 HomoloGene: 9457 ChEMBL: 1075132 GeneCards: TRAP1 Gene
[show]Gene Ontology
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	10131	68015
Ensembl	ENSG00000126602	ENSMUSG00000005981
UniProt	Q12931	Q9CQN1
RefSeq (mRNA)	NM_001272049	NM_026508
RefSeq (protein)	NP_001258978	NP_080784
Location (UCSC)	Chr 16: 3.7 – 3.77 Mb	Chr 16: 4.04 – 4.08 Mb
PubMed search	[1]	[2]

Heat shock protein 75 kDa, mitochondrial is a protein that in humans is encoded by the TRAP1 gene.^[1][2][3]

THESE 4 GENES NEEDS TO BE LOOKED AT ASAP IN TRIPLE NEGATIVE BREAST CANCER WITH BASALOID MORPHOLOGY!

INTERESTING ARTICLES. GO TO THEM!

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

Cancer Research, 02/21/2013 

(APPARANTLY THIS IS NOT FOUND NATURALLY IN NORMAL BLOOD)

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

Annals of Oncology   02/06/2013

STUDY COMPLETED IN KOREA

NOMENCLATURE OF GENES TO LOOK FOR IN TRIPLE NEGATIVE BREAST CANCER

One may try to determine whether a breast cancer has bad prognosis in order to determine whether chemotherapy should be given (MammaPrint, Oncotypr DX), but more importantly, I believe, is to focus on genes of good prognosis which include driver genes against which we dispose of an answer in our Arsenal.
Currently we dispose of
1. Chemotherapy that attacks DNA and Microfilament/Microtubules,  (first and second law of nature)
2. Immune Modulators such as Interferon
3. Antibody to Membrane Receptor (EGFR/VEGF) Avastin
4.  Inhibitor to T-cell driven immunity (CTLA4)
5.  Inhibitors to sub-membrane or first line driver Mutations KRAS, HRAS, or the RAS family
6.  Inhibitors to 2nd line driver Mutations (anti MEK)
7. Inhibitor to Tertiary line driver Mutations and Mitochondrial level inhibition (MTOR, Metformin)
8. Anti-proteasome or inhibitor to cellular protein degradation (Velcade)
9. Inhibitors at Nuclear lever Include Histone Deacethylator and Acyl transferase inhibitor, check point controller inhibitors,  anti-Centrosome metabolism and inhibitors of various promoters and transcription factors.

Other opportunities not included in this classification go to specific genes of proliferation, Amplification, differentiation and metastasis that have been brought forth as indicator of either response to chemotherapy or simply as "Good prognosis" genes.  These will include the BRCA since a response to PARP inhibitors and Cisplatin based combinations should be anticipated.

Multikinase inhibitors such as Dasatinib (SRC+ BCR/ABL but also STAT5) and Arsenic Trioxide should be included   
LBK1: could predict early disease (inhibitor controlling initiation of metastasis)
DDR2: could predict anti MEK sensitivity
MEKK-1 sensitivity to Cisplatin
TFF1-could predict sensitivity to estrogen despite negative Estrogen
DYRK2, favorable in lung cancer
 
c-JUN amplification and over expression of 8q23-24 could predict  response to interferon/Interleukin
EGFR, VEGF, ALK,  and other Driver Mutations would match those discussed By DR Kris in lung cancer.

(to be continued!)

PUTTING THINGS TOGETHER IN TRIPLE NEGATIVE BREAST CANCER BRCA TESTING AND THE MTOR UNVEIL NEW PARADIGM SHIFT AT CRBCM

Now that we know that up to 85% of triple negative Breast cancers could have the BRCA Mutation in some cohort,  it is becoming a guideline shift that this test be performed not only for prognosis, but also for therapeutic information.  The presence of BRCA positivity generally imparts worse prognosis of this disease.
But knowing if it is BRCA1 positive will give it an atypical morphology as per  the article from Stanford suggests:

"The luminal A subtype of breast cancer had the highest frequency of PIK3CA mutation (45%), and the basal subtype had the lowest (9%). These data are consistent with the results of prior studies, as luminal A and basal-like subtypes roughly correspond to ER-positive and triple-negative breast cancer by immunohistochemistry (IHC), respectively. Even though PIK3CA mutations are oncogenic, they are a good prognostic factor and are associated with improved survival.[12] This is important to consider when assessing patient survival in trials in patients with PIK3CA mutations."

BRCA 2 is mostly of Luminal histology and therefore will be more susceptible to PIK3CA/MTOR blockade which will explain their better prognosis.  We still believe that as we move forward, the role of interferon and Mtor is still to be explored.  As that in Luminal triple negative BRAC2 positive hormone manipulation with MTOR could still be tried. We still believe that EGFR inhibitor in combination to MTOR inhibitor and inhibitor of NK-kB or antiproteasome are all potential add-ons!

MICROSATELLITE INSTABILITY IN TRIPLE NEGATIVE BREAST CANCER?.

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

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

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

TRIPLE NEGATIVE BREAST CANCER, A MELTING POT

The news that the Genome of triple negative breast cancer is similar to ovarian cancer has been good as a starting point. But that is as far as it goes!  Researcher are now scrambling trying to see how to best use this information and there is not one good direction.  In fact if anything, it may have complicated the landscape.
The controversy is compounded by the news that there is not simply a single type of Triple Negative Breast cancer.  This added to the fact that there is not just one type of Ovarian cancer.  So which one is the best approach?  And there are no known good suggestions, because of a lack of comprehensive database for cancer types.  Our cancer knowledge is disconnected.  Someone knows more about this. Someone else knows about that. There are Gaps in the knowledge which prevents us from moving forward.

Some of the facts and knowledge:

1. That the Genome is similar to Ovarian Cancer.
2. That Taxane-Cisplatin works in Ovarian Cancer
3. That PARP may have a role
4. That (low) MEKK1 expression is linked to tumor Response to Cisplatin.
5. That BRAC may impart a poor prognosis to the tumor
6. That Downregulation of STAT1 may play a role in the Oncogenesis of Triple Negative Breast cancer.
7. The almost total lack of Role of P53 alteration
8. Limited role of Kras Mutation
etc.

There are Major Questions of therapeutic importance:

1.Are these cancers MUCINOUS? Is there presence of MUC family members?
If these tumors are mucinous, this is another bad news.  Mucin presence shields against detection by the innate immune system and favors cancer dissemination to go undetected.  Mucin contains molecules that interfere with Glycocalyx, blunting their ability to expose cancer cells to the immune system, and also contain molecules full of Sulfhydryl expressing molecules which have profound interaction with electron based reactions at the membrane and Intracellularly.  These activities are generally protective for the cancer cell.

The Mucinous presence can also be supported by the presence of Galectin 4 (LGALS4)  19q13.3 (Heterozygosity site).   Positive TFF1 of the trefoil factor family which is an Estrogen regulated molecule that could potentially predict some response to hormone manipulation even in triple negative setting.

Amplification of CDX which modulate proliferation, cell adhesion and Apoptosis.  The fact is this CDX could be a driver phenomena as this cancer is known for its ability to have a steady progression.

OTHER Molecules of Importance CDH17, Tetraspanin, MSF1R, E-Cadherin and the Kruppel like factor.

2. These tumors seems to have a survival that is epic, raising the issue of expression of survival pathways MEK, MAP Kinases and C-jun
3. What differentiates Endometrioid Vs other ovarian cancers will play a role in this disease
4. What is the role of target therapy, important in Ovarian cancer, as it relates to Triple negative breast cancer?

We are only just scratching the surface of this problem,
Time to put the puzzle together!

In a recent Article published in the December 15th ASCO POST,  Lina Baumbach-Reardon, PhD discussing Triple Negative Breast cancer reported differences of gene expression in 2 small cohorts of patients, one from Kenya and one from African Americans in the United States.   Given the size of the cohorts reported, no conclusion can really be drawn, but I agree that it is a teaser!

It also brings back to the surface many questions about where the African American population was pulled from originally and what kind of brassage or mix has occurred since then.  Recognition that patterns of Breast cancer mortality observed in African Americans  is similar to that of "Hispanic" populations, raises questions.  The Breast Cancer "incidence-Mortality paradox " is true for both populations.
Suffice is to say that there is more to find out.  Coming from the Congo, the CRBCM would push for this kind of studies if funds were allowed in the future. This brings up this: (from yahoo)
--------------------------------
   Congo-Kinshasa: African Union Holds Talks on 'Neutral Force' Wed, 09 Jan, 2013 02:27 AM PST
[African Union]Addis Ababa -As a follow-up to the recommendations of the consultative meeting on the operationalization of the security arrangements agreed to in Eastern Democratic Republic of Congo (DRC), held in Addis Ababa, on 27 and 28 December 2012, a ministerial meeting of the countries of the region and international partners took place at the African Union (AU) Headquarters, in Addis ...
UN Seeks Surveillance Drones for Eastern Congo
Wed, 09 Jan, 2013 02:12 AM PST
United Nations peacekeepers are asking the Security Council to support the use of surveillance drones in the eastern Democratic Republic of Congo. U.N. peacekeeping chief Herve Ladsous appealed to the council in a closed-door session Tuesday, seeking the drones to help the more than 17,000 peacekeepers in the country. Rebels briefly took control of the eastern city of Goma late last year after ... Rwanda opposes use of drones by the UN in eastern Congo
reuters.com Wed, 09 Jan, 2013 01:02 AM PST
UNITED NATIONS (Reuters) - Rwanda on Tuesday opposed the use of surveillance drones in eastern Congo as proposed by the United Nations until there is a full assessment of their use, saying it did not want Africa to become a laboratory for foreign intelligence devices. Envoys said U.N. peacekeeping chief Herve Ladsous told the Security Council during a closed-door session that the U.N mission in ...

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AND THE FIGHT GOES ON!

 

COMBINATION OF XELODA, AND ANTICALMODULIN AND AN ANTI-P35 ANTIBODY FOR TRIPLE NEGATIVE BREAST CANCER.,

OR TAXOTERE-XELODA-VELCADE-ANTI-P35

If the fighting cancer strategy is to disrupt the cell where it hurts the most, the above combinations make the most sense.  These combinations achieve the following:

1.  Disruption of Microfilaments/Microtubules which in turn disrupt Anaphases in dividing cancer cells.  This also disrupts membrane attachment of  Cytochromes in Mitochondria by disrupting the Cytoskeleton, and leads to Caspase release.
2. Xeloda leads to an increase of intracellular 5-FU and to DNA breakage which triggers activation of P53 induced stoppage of cell division.
3. The Anti-Calmodulin will add and increase an intracellular release of Calcium leading to stimulation of Endonucleases which will further damage the DNA.
4. The Anti-P35 decreases resistance to Caspases since P35 is an inhibitor of  Caspases.
5. To lead to growth advantage, most cancers get a mutation of the MDM2 which leads to increased ubiquitination proteins/cyclins  favorable to apoptosis, making Velcade a powerful drug as it disrupts the proteasomes!

With these combinations, we are trying to harvest the strongest destructive forces in a cell!

Translational Research Project

Research at CRBCM

The CRBCM has determined that Breast Cancer Mortality in African American is excessive.  Of the 6000 African American women who will or have died this year, 3000 could have been saved if leaders paid more attention to this cause.
3 reasons  contribute to this excess mortality
1. Poor rates of screening mammograms in these minority population (or low income populations in general).
2. Late stage of disease at diagnosis
3. POOR HISTOLOGY, high rate of triple negative Breast cancer, which can only be managed by adjuvant and palliative chemotherapy.  Increasingly however, new target treatments are being tried. (ie.PARP and Histone De-acetylator inhibitors).

The success of chemotherapy, the only option readily available to African American women with triple negative Breast cancer is 20-40% at best.  We need further options and further investigation is required.
At CRBCM we believe that the potential contribution of Anti-Kinesin could be even more important, particularly when combined to a Taxane-Cisplatin or related Microtubule disrupting drugs.

The human Genome Project has already determined that the Genome of triple negative Breast Cancer is comparable to that of Ovarian Cancer.This fact re-enforces our choice for Taxane-platinum based combination in this disease.
Another thing we know is that cure happens when the cancer cell is killed.  The killing of cells is induced by Caspase release from cellular mitochondria.  Caspases are lytic proteins to the extent of achieving death by global disruption of sensitive pathways.  To our knowledge one of the determinant inhibitor of Caspase release is the presence of high levels of Bcl-2.  Bcl-2 seems to be more effective in mitigating the effect of drugs acting through the Topoisomerase enzyme (etoposide and Adriamycin)

In a cell such as the cancer cell which naturally intend to divide for growth of the cancer, disruption of Microtubule/microfilament, support scaffolding  for movement of chromosomes during cell division, appears a stronger argument bypassing the Bcl-2 protection for the release of caspases.  In fact, the Mitochondria nearby appear to be located there attached to close-by membranes.  Suffice is to say that significant microtubular or Microfilament  disruption  is not compatible with life.  This is why Taxanes (Erubulin and Ixabepilone) are most likely the most powerful drugs in breast cancer.  It is also why we believe that the right Anti-kinesin could add significantly to the effect of Taxane-platinum combination in triple negative Breast cancer.

Study Methology

1 We will use 50 tissue sample of 4 different cancers (Breast, Colon, lung and liver) for a total of 200 tissue samples.
2.Using Bcl-2 kits, we will detect and quantify Bcl-2 per tissue and per nature of tissue origin.  We can then identify which type of tissue has the highest Bcl-2 at cancerous status.
3.we will expose half of each group of tissue to taxal-Cisplatin ex-vivo. and, using standard kits, will detect and quantify Caspases released.
4. we will expose the other half to a triplet with Taxane-Cisplatin and Antikinesin, and detect and measure quantitatively the level of Caspases released by the tissue
5. Consideration of using Antikinesin alone has been discussed, no one would choose this option given the fact that time and again mono-target therapy have failed to achieve better than 30% because of patient genome heterogeneity.
6. We could also test these tissue response to Etoposide to verify Bcl-2 resistance and therefore appreciate the magnitude of Microtubule disruptions through the Taxane based combinations.

Our conclusions (proof of concept) will relate to:

1. Bcl-2 content by nature of the cancerous tissue.  This would predict sensitivity to tested chemotherapy drugs.
2. Verify sensitivity and specificity of Bcl-2 kits
3. Verify sensitivity and specificity of Caspase kits
4.Verify that Taxane-platinum based chemotherapy is better than Etoposide Ex-vivo.
5.Verify that adding Anti-kinesin improves response to therapy
6. By comparing to Etoposide alone by levels of Bcl-2, verify that Taxane based combination do bypass Bcl-2 protection of Mitochondria
7. If differences are corroborated, we can show that response to therapy can be predicted ex-vivo.

It is evident that such a study provide numerous commercial opportunities when it comes to kit development and Antikinesin  product selections.

Let's work with this Peggy! add any ideas and suggestions
we ask our readers to send their comments. The fight is on for the cure...

PARP Inhibitors

PARP
Day 2 went very well in Houston
made it on time
in the meantime received positive news from El Paso
can apply for faculty time in clinic at University Medical Center
will be an honor if it gets through'
willing to cover at another Hospital over coming holidays to broaden my share of patients
while veterans physicians take it easy...will use any opportunity to shine.

Now Back to PARP inhibitor, (Poly ADP Ribose Polymerase), they are powerful drugs which follow our first law, they break DNA or cause failure to repair DNA mistakes.  Therefore cause automatic activation of intact P53 to induce automatic cell division Arrest. In other words, they act like Cisplatin and therefore will have a role in Ovarian cancer and by inference, will have a role in basal cell like Breast cancer (or triple negative Breast cancer).   Again, their limitation depend on preservation of P53 and all other molecules of that cascade.  They will also be limited by how fast the cell makes its repair.

Remember the 2nd law is the break of Microtubules/Microfilaments that leads to direct Caspase release, more powerful law.  This implies that a combination of PARP with Taxane (or Ixabepilone or Erubilin)will be the next non platinum combination of significance.

Following this logic, we predict an expanded role to Arsenic trioxyde. But fear of its use resides in its cardiac toxicity. But it acts like a Multikinase inhibitor because it interferes with so many cascades in the signal transduction.  Its limitation could also be that it may not lend itself to combination therapy because of "assumed" risk to the host.