4 Posters at 1st BIOMED Symposium, El Paso 10/26/2013

Dr.Zhang and Dr.Kankonde, Early Detection of Lung Cancer

 

 Dr. Kankonde, Immunotherapy in Ovarian Cancer

Dr.Kankonde, Decrease of TBI by early use of Butein, a Sirtuin Activator

 

Dr.Kankonde at 1st BIOMED Symposium El Paso, 10/26/2013

 

Dr.Zhang, UTEP, and Peggy Kankonde, Greater East Cancer Center

Progress in Genome studies: case in point the DIGITAL PCR.

If what they promise is real, we are entering an important phase where not only we can count mutations,  but can also try to determine levels of gene amplifications  that are secondary, versus those that are in response or a consequence of upstream genes normally amplified or amplified because they are mutated!

" Next-generation sequencing technology has transformed cancer genomics, but faces the challenge of genome and transcriptome heterogeneity inherent to any tumor sample. One strategy for capturing the complex landscape of mutational processes, clonal evolution/amplification and tissue invasion is the application of digital PCR, which enables the identification and precise quantitation of individual mutations - including those present at a very low frequency."(Biomedcentral)

This new technology will open new evaluations of gene quantities as to their meaning and trigger!  It will allow also to detect levels of suppression of a normal gene when it is found in an unexpected amount.  We know for example that in many lung cancers PTEN is suppressed.  Whether  this is a primary happening or secondary can be further debated.  In Ovarian cancer DAB2 is suppressed. ("The down-regulation of DAB2 may play an important role in ovarian carcinogenesis. This gene was initially named DOC2 (for Differentially expressed in Ovarian Cancer) and is distinct from the DOC2A and DOC2B genes (for double C2-like domains, alpha and beta).^[3]

 Most of these suppressions are the result of an amplification of an upstream gene or an overexpression of an inhibitory protein.  When it comes to DAB2, it is important to report that this gives the cancerous process some teeth and bad prognosis.  Indeed, the suppression of DOC2 gives the tumor ways of escaping proliferation control by the cancerous cell by activating E3 (removing by unbiquitilation of the inhibitor of the inhibitor of E3).  This new technology will allow direct quantification of the 2 inhibitors or the E3 for that matter.  It may also clarify how Velcade works in relation to the 3 compounds!

T-DM1 IS NOT ALONE AND TARGET THERAPY WILL LEAD US TO NEW MEDICATION EVERYDAY : GET THIS!

"DMUC5754A consists of a monoclonal antibody against the protein MUC16, found on ovarian cancer cells at high levels, and a toxin linked by a cleavable linker. Approximately 80% of ovarian cancer patients have tumors that have high expression of MUC16 (also known as CA-125), according to Liu. The toxin is the microtubule-disrupting agent monomethyl auristatin E (MMAE). The antibody directs the toxin specifically to ovarian cancer cells to kill them. Because the antibody delivers the toxin specifically to the ovarian tumor, an especially potent toxin can be used, one that would be too toxic as a general cytotoxic agent that would also affect healthy tissue." NEWS FROM GENENTEC SOURCE

 

Home » CONFERENCES » AACR 2013

CONFERENCE REPORT  AACR: Antibody-Drug Conjugate Shows Promise in Platinum-Resistant Ovarian Cancer By Anna Azvolinsky, PhD1 | April 9, 2013 1Freelance Science Writer and Cancer Network Contributor. Follow Her on Twitter Washington, DC—A novel therapy has shown activity in treatment of difficult-to-treat, advanced, platinum-resistant ovarian cancer. The drug, DMUC5754A (Genentech), is part of a new class of drugs called antibody-drug conjugates. The phase I trial results were presented at the American Association for Cancer Research (AACR) Annual Meeting, held April 6–10 in Washington, DC by Joyce F. Liu, MD, MPH, of the Dana-Farber Cancer Institute and Harvard Medical School in Boston. Ovarian cancer as seen on CT; source: James Heilman, MD, Wikimedia Commons “Overall the drug was well tolerated, with a toxicity profile that is comparable to other therapeutics currently used in clinical practice,” Liu told Cancer Network. “We think the results are very encouraging in a patient population where response to other therapies is limited.” (MORE: AACR: Anti-PI3K/MEK Inhibitor Targeted Therapy Combo Shows Activity) DMUC5754A consists of a monoclonal antibody against the protein MUC16, found on ovarian cancer cells at high levels, and a toxin linked by a cleavable linker. Approximately 80% of ovarian cancer patients have tumors that have high expression of MUC16 (also known as CA-125), according to Liu. The toxin is the microtubule-disrupting agent monomethyl auristatin E (MMAE). The antibody directs the toxin specifically to ovarian cancer cells to kill them. Because the antibody delivers the toxin specifically to the ovarian tumor, an especially potent toxin can be used, one that would be too toxic as a general cytotoxic agent that would also affect healthy tissue. The results from the phase I trial also showed that those patients who had the highest expression of MUC16, the target of the antibody portion of the drug, derived the most benefit from the treatment. This is likely to facilitate the selection of only those patients who are most likely to benefit from treatment in future trials. Platinum-resistant, advanced ovarian cancer has an unmet need and is difficult to treat. Patients currently have few treatment options. Platinum-based chemotherapy remains the standard way to treat ovarian cancer, and platinum resistance is a major treatment challenge. The phase I trial evaluated various doses of DMUC5754A in advanced ovarian and pancreatic cancer patients. DMUC5754A was administered at doses ranging from 0.3 mg/kg to 3.2 mg/kg every 3 weeks. Forty-four patients with advanced, recurrent, platinum-resistant ovarian cancer enrolled; of those, one complete response and four partial responses were reported. All patients who responded were treated with a 2.4 mg/kg dose of the drug and had high MUC16 expression in their tumor cells. Six additional patients had minor responses. Fatigue was the most common adverse event at all dose levels, occurring in more than half of all patients. Other common adverse events were vomiting, decreased appetite, nausea, diarrhea, and peripheral neuropathy. Peripheral neuropathy was manageable and reversible in most patients through dose delay and dose reductions, according to the researchers. Grade 3 adverse events included fatigue and neutropenia, both occurring in 9% of patients. Neutropenia and uric acid release were the only dose-limiting toxicities during the study. Both occurred at the maximum 3.2 mg/kg dose. Other serious drug-related adverse events were small intestine obstruction in two patients, hypocalcemia in a single patient, and neutropenia in a single patient. “Neuropathy, which was an anticipated potential toxicity of the drug, did occur, but was manageable and typically reversible with dose reductions or delays,” said Liu. The role of MUC16 in cancer development and progression is not yet clear. The protein is a large transmembrane protein that is found in abundance on ovarian cancer cells but not healthy tissue. Researchers speculate that the protein may help ovarian tumor cells bind to mesothelial cells that line the peritoneal cavity. The encouraging activity and safety profile of the antibody-drug conjugate warrants further trials in ovarian cancer patients, according to the study researchers. “I think the major remaining question is how this therapy compares against the standard treatments that we use in platinum-resistant ovarian cancer,” said Liu. Discussions for further development of DMUC5754A, including a phase II ovarian cancer trial, are ongoing.

STRATIFIN (IN OVARIAN CANCER)

LAM et al.

 " Stratifin, also known as 14-3-3 sigma protein, stimulates matrix metalloproteinase (MMP)-1 expression in dermal fibroblasts.  Treatment of dermal fibroblasts with stratifin resulted in rapid and transient upregulation of c-jun and c-fos mRNA levels.  Stratifin was demonstrated to increase MMP-1 protein levels. Microarray analysis of stratifin-treated fibroblasts shows an increase in Elk4/Sap1 mRNA expression and this finding was confirmed by northern blot analysis. Our results indicate that stratifin markedly increase Elk4/Sap1 mRNA expression in a time-dependent fashion. In conclusion, stratifin stimulates fibroblast MMP-1 levels through the activation of c-fos and MAPK pathway."

Our interpretation is that stratifin is part of an intergrin, its release in the Cytoplasm indeed stimulate MAPK C-JUN and c-fos.  This means it is interpretated by the cell as a chemical stressor. The NF-kB is not far away.  One of the most important hidden information here is the note by the authors that there is an increase of ELK4/Sap1.

ELK4 has been shown to interact with Serum response factor^[4][5] and BRCA1.^[6]

Serum response factor has been shown to interact with NFYA,^[10] Src,^[11] CREB-binding protein,^[12] GTF2I,^[13][14] ATF6,^[15] Nuclear receptor co-repressor 2,^[16] CEBPB,^[17][18] GATA4,^[19][20] Myogenin,^[21][22] GTF2F1,^[23][24] TEAD1,^[25] ELK4,^[15][26] Promyelocytic leukemia protein^[12] and ASCC3.^[27]

(wikipedia)

(PLEASE, WHEN A MOLECULE INTERACT WITH THIS MANY MOLECULE, IT IS A PERFECT, LEGITIMATE TARGET FOR THERAPY, AND SFR DOES)

ELK4 therefore control BRCA1 and serum response factor which control NFYA.  This uncover what the cancer cell has to do to start the neoplastic process.  It has to derail genetic repair by abrogating the action of BRAC1, but it also has to take controles of CBF complexes  and NFYA and ZHXY.  Remember CBF complexes control the direction of the metabolism, In essence, when it comes to function in the cell,  the role of Core Binding Factors (CBF) is indistinguishable from that of TRANSCRIPTION FACTORS.  They all impose the direction that the cell metabolism should take.

Remember also that because the Stratifin engages the MAPK mostly through the certain well selected CDK, it will tend to stop cell division.  In Breast cancer, Stratifin is one of the earliest methylated gene slated for silencing.

CDO1:
 Cysteine dioxygenase type I, IS A GENE CONTROLLING  CYSTEIN METABOLISM. DEEP ANALYSIS BRINGS THIS GENE TO ELECTRON EXCHANGE FOR THE FORMATION OF CYTOCHROME C, THE WAY TO APOPTOSIS.  THE CANCER CELL QUICKLY METHYLATES THIS GENE EARLY AND MUTATION HAS BEEN LINKED TO PROGNOSIS
 (WORK FROM CORNELL UNIVERSITY)

Nomenclature of 2 important genes in Ovarian cancer !

1.RASSF1A:  One of the thing cancer cell do is to Methylate some genes in order to block its path to death.
it appears this gene is a critical door to shut or disable.  It not only decrease the significance of RAS and MAPK in the pathogenesis of tumor that harbor this mutation.   It also remove blockage to proliferation by desensitizing the cell to the effect of P53, Cyclins.  Desensitize the cell to Death Receptor 6 and its Fas connection.  RASSF1a, demethylation is a valid target in ovarian cancer.

2.HNF1B:  " Hepatocyte Nuclear Factor 1α (HNF1α) is an atypical homeodomain-containing transcription factor that transactivates liver-specific genes including albumin, α-1-antitrypsin and α- and β-fibrinogen. Biallelic inactivating mutations of HNF1A have been frequently identified in hepatocellular adenomas (HCA), rare benign liver tumors usually developed in women under oral contraceptives, and in rare cases of hepatocellular carcinomas developed in non-cirrhotic liver. HNF1α-mutated HCA (H-HCA) are characterized by a marked steatosis and show activation of glycolysis, lipogenesis, translational machinery and mTOR pathway. We studied the consequences of HNF1α silencing in hepatic cell lines, HepG2 and Hep3B and we reproduced most of the deregulations identified in H-HCA."
 (Laura Pelletier et al)
This gene is the gene of differentiation for liver formation, it has the structure of a CBF (core binding Factor) therefore has a subunit binding the DNA, therefore silencing that portion, and another subunit having locations for enzymatic proteins or molecular structures that directly assume various functions intended by the cell (formation of Albumin, alpha Antitrypsine, and Beta Fibrinogen).
Interestingly enough, Steatosis is a prominent feature here.  This structure and gene may be of interest in LIPOSARCOMA?  
DOES ACTIVATION OF MTOR DEMONSTRATED HERE OPEN THE DOOR TO THE USE OF MTOR IN LIPOSARCOMA?

Nomenclature of some Genes in Ovarian Cancer:

Nomenclature of some Genes in Ovarian Cancer:

BRAC1
BRAC2
CDO1
HER-2
CPG ISLAND
TMS1
ER alpha
PRB
MEK
==============================================================
RASSF1A:  One of the thing cancer cell do is to Methylate some genes in order to block its path to death.
it appears this gene is a critical door to shut or disable.  It not only decrease the significance of RAS and MAPK in the pathogenesis of tumor that harbor this mutation.   It also remove blockage to proliferation by desensitizing the cell to the effect of P53, Cyclins.  Desensititize the cell to Death Receptor 6 and its Fas connection.  RASSF1a, demethylation is a valid target in ovarian cancer
RARbeta
=============================================================

STRATIFIN.

LAM et al.

 " stratifin, also known as 14-3-3 sigma protein, stimulates matrix metalloproteinase (MMP)-1 expression in dermal fibroblasts.  Treatment of dermal fibroblasts with stratifin resulted in rapid and transient upregulation of c-jun and c-fos mRNA levels.  Stratifin was demonstrated to increase MMP-1 protein levels. Microarray analysis of stratifin-treated fibroblasts shows an increase in Elk4/Sap1 mRNA expression and this finding was confirmed by northern blot analysis. Our results indicate that stratifin markedly increase Elk4/Sap1 mRNA expression in a time-dependent fashion. In conclusion, stratifin stimulates fibroblast MMP-1 levels through the activation of c-fos and MAPK pathway."

Our interpretation is that stratifin is part of an intergrin, its release in the Cytoplasm indeed stimulate MAPK C-JUN and c-fos.  This means it is interpretated by the cell as a chemical stressor. The NF-kB is not far away.  One of the most important hidden information here is the note by the authors that there is an increase of ELK4/Sap1.

ELK4 has been shown to interact with Serum response factor^[4][5] and BRCA1.^[6]

Serum response factor has been shown to interact with NFYA,^[10] Src,^[11] CREB-binding protein,^[12] GTF2I,^[13][14] ATF6,^[15] Nuclear receptor co-repressor 2,^[16] CEBPB,^[17][18] GATA4,^[19][20] Myogenin,^[21][22] GTF2F1,^[23][24] TEAD1,^[25] ELK4,^[15][26] Promyelocytic leukemia protein^[12] and ASCC3.^[27]

(wikipedia)

ELK4 therefore control BRCA1 and serum response factor which control NFYA.  This uncover what the cancer cell has to do to start the neoplastic process.  It has to derail genetic repair by abrogating the action of BRAC1, but it also has to take controles of CBF complexes  and NFYA and ZHXY.  Remember CBF complexes control the direction of the metabolism, In essence, when it comes to function in the cell,  the role of Core Binding Factors (CBF) is indistinguishable from that of TRANSCRIPTION FACTORS.  They all impose the direction that the cell metabolism should take.

Remember also that because the Stratifin engages the MAPK mostly through the certain well selected CDK, it will tend to stop cell division.  In Breast cancer, Stratifin is one of the earliest methylated gene slated for silencing.

======================================================================
HNF1B " Hepatocyte Nuclear Factor 1α (HNF1α) is an atypical homeodomain-containing transcription factor that transactivates liver-specific genes including albumin, α-1-antitrypsin and α- and β-fibrinogen. Biallelic inactivating mutations of HNF1A have been frequently identified in hepatocellular adenomas (HCA), rare benign liver tumors usually developed in women under oral contraceptives, and in rare cases of hepatocellular carcinomas developed in non-cirrhotic liver. HNF1α-mutated HCA (H-HCA) are characterized by a marked steatosis and show activation of glycolysis, lipogenesis, translational machinery and mTOR pathway. We studied the consequences of HNF1α silencing in hepatic cell lines, HepG2 and Hep3B and we reproduced most of the deregulations identified in H-HCA."
 (Laura Pelletier et al)
 This gene is the a gene of differentiation for liver formation, it has the structure of a CBF (core binding Factor) therefore has a subunit binding the DNA therefore silencing that portion, and another subunit having locations for enzymatic proteins or molecular structures that direct assume various functions intended by the cell (formation of Albumin,alpha Antitrypsine, and Beta Fibrinogen)  Interestingly enough, Steatosi is a prominent feature here.  This structure and gene may be of interest in LIPOSARCOMA.?   DOES ACTIVATION OF MTOR DEMONSTRATED HERE OPEN THE DOOR TO USE OF MTOR IN LIPOSARCOMA?
-------------------------------------------------------------------------------------------------------------
p16INK4A
p14
CYCLIN D2
SLIT2
CDH13
PTEN
CLAUDIN 3,4
HE4
MUCIN1 OR MUC1
MESOTHELIN
ApoE, J
PIK3CA
P53 AND CHEK2
MLH1
MSH2,6
PMS2
CA-125
STK11
LKB1
PTCH
ATM

This is just the beginning, lets go to work! love those recurring genes as they cross over with presence in other cancers to strengthen their importance, Please remember those that lead to hypothrophy of muscles and extremities are probably more important for therapeutic intervention.  And those with a "q" location on chromosome arm are most likely of poor prognosis or dramatic phenotype expression!  Always do remember that Multidrug resistance (MDR-1) is in play  HERE!

GENES IN OVARIAN CANCER: (part I)

The notion that there is a particular gene or genes for a specific cancer is attractive, but most of the time only reflects the scientists' tendency to attract the community interest on their findings.  There is nothing wrong with that because their work needs recognition. Recent advances in cure and novel therapeutic approaches have occurred to convince the common of mortals that Researchers are hard at work.  But by now we know that most standard genetic family abnormalities involve only 5-10% of cancers.  That means that no one genetic abnormality stands to justify any specific cancer in-toto. The case of BRCA1 and 2 in Breast cancer.
Breast cancer survivor Women who participated in My talk in El Paso,TX were surprised to learn that 85% of women newly diagnosed with Breast cancer in the US were first in their family.  Everybody was assuming that breast cancer happens because of family predisposition.  This is clearly an underestimation of the heterogeneity of our genetic material.  Don't understand me wrong, there are clear cases of family predispositions, however, we have an approximate 25,000 genes, something and somewhere a significant event can happen anytime.  Also, one should know that there is primary and secondary amplification.  In some cases it is hard to determine which came first (Chicken and egg dilemma ).
Another compounding factor complicating our interpretation in rare cases, is the notion that the cause of cancer can be located in the promoter gene which all of a sudden becomes difficult to methylate or suppress, causing secondary amplification of a gene or of its regulators.
When one wants to look at the genes involved in ovarian cancers, it is good to focus on particular genes (HNF1B) as clearly publicized, but we can't ignore the story of BRCAs, and other family syndromes which harbor Ovarian cancer as a component of the syndrome.  Therapies that are being developed and being effective in Ovarian cancer (Anti MEK) are also pointing to relevant genes.   The story of lung cancer with its ever expanding list of DRIVER MUTATIONS and the advent of MULTIPLEX gene screening is just another proof of the danger of claiming to have discovered THE GENE for a specific cancer!

GENES OF OVARIAN CANCER (to follow)

Ovarian Cancer

*Researchers who conducted the study who conducted the use of Selumetinib in low grade serous Ovarian cancer were still puzzled because its activity did not follow presence of KRAS or BRAF. They have been wondering if it used another pathway.  But remember MEK is the revolving door to de-differentiation and to the reversal of mesengialization and as such increase tor susceptibility not only to chemotherapy drugs, but also to the secondary angiogenic potentiation of MEK.  That is, with anti-MEK, there is a down regulation of MAPK (as suggested) and therefore  the C-JUN and TGF and cyclins, but also down regulation of the VEGF!

They say " Our results suggest that selumetinib is an active agent, but not necessarily because of BRAF or KRAS mutational activation per se,” the authors concluded.

In an interview, Gershenson said that one reason for the lack of correlation could be biomarker instability. Among the 52 patients, specimens were available for only 40, mutational analysis was done in 34, and in 28 of those the tissue was from the primary therapy and not from the recurrent tumor. “The question arises, are these biomarkers stable over time or do they change, so that what you find in the primary tumor may not be what you find in the recurrent tumor,” he said."   They suggesting here that the lack of correlation could be due to a changing nature of Biomarker.  But the existence of other factors and pathways could not be be excluded!

Gene-Expression Profiling May Help Select Best Drugs for Pancreatic Cancer

Caroline Helwick 

---------------------------------------------------------------------------------------------------

In this study patient with pancreatic cancer had reportedly circulating cell and their genes could predict response to therapy but unfortunately they did not spell out which genes were reviewed.  We will investigate further this article...

PROOF OF CONCEPTS: THE CASE OF PANCREATIC CANCER

1.  "P" ARM VERSUS  "Q"
-----------------------------
As you look at the location of Genes, one will quickly notice that various genes have their family counterpart not close on the same chromosome. But instead on a different chromosome altogether.  In general we almost treat this  information in a profane manner in that we overlook the meaning of this.  Nature, however, has no place for randomness. Everything has deep meaning and NUANCES OR MINIMAL VARIATIONS can make a world of difference. Should you doubt this statement, ask the people with Sickle cell, they are not laughing about that nuance in Hemoglobins.  So when a family member has put in a different chromosome, there is no pun intended.

ERBB1 is on chromosome 7p12 (involved in Glioblastoma and Squamous cell head and neck cancers)
ERBB2 is on chromosome 17q11.2-q12 (involved in breast, Ovarian and cervical cancer)

Also however, we note that the family member is put on a "p" rather than "q" location.  This also has a profound meaning.   It just turn out that mutation on "q" location seems to have the worse prognosis and are more likely to be expressed  than those on "p" location.

The bad guy MYC is located 8q24 and is found on advanced forms of cancers (Ovarian, Breast, small cell, Esophageal and cervical but also in the Burkitt (ALL))
The nice MYCN, often a better prognosis indicator, is located on 2p24  but still can be involved in Neurobalstoma.

These are in fact speculation but check it out!

Another example
just go ahead and compare
breast cancer with FGFR1 located 8p11
and breast cancer with EGFR1 located 10q25
and call me if you find different!

PROOF OF CONCEPT NEEDED FOR PANCREATIC CANCER:

One of the complication or hurdle you encounter when you are dealing with abnormal genes
in pancreatic cancers is the the genes found in abnormal cancers are also found in benign conditions such as Adenoma or even pancreatitis.  Now if we assume that this is an Adenocarcinoma of the same origin embryonically as the colon (check that assumption out), we could apply the colon cancer model where
EARLY CANCER FOR ADENOCARCINOMA IS ANNOUNCED BY LOSS OR MUTATION IN CHROMOSOME 17:   IE GENES     (FOLLOWING THE COLON MODEL)
-----------------------------------
-KRT20
-TEM 7
-MAP2K4
BAT-26
ALOX 12
TP53
BIRC5
NME1
ERBB2
GAS
TM4SF5

LATE CANCER,  LOSS OF CHROMOSOME 8 (FOLLOWING THE COLON MODEL)

CDH4
PSCA
MYC
 (FGFR1 AND BAG4 ARE HAVE A "p" LOCATION ON THE CHROMOSOSME)

Fresh from ONCOFACTS

Low Grade Serous Ovarian Cancers Respond to Selumetinib
The GOG is conducting a phase II study of low grade serous ovarian cancers, which when recurrent are usually resistant to both hormonal therapy and chemotherapy. Patients with low grade serous ovarian cancer received selumetinib, an oral small molecule inhibitor of MEK 1 and 2, part of the MAP-Kinase pathway.
Of 52 patients treated with selumetinib, all had had at least one prior systemic therapy and 15% achieved a PR while 65% maintained Stable Disease. Median PFS was 11 months and two year OS was 55%.
While 14 patients had KRAS mutations and 2 had BRAF mutations, there did not appear to be any correlation between mutation status and response. A larger phase II-III clinical trial is beginning.

FDA APPROVED THE GENERIC DOXIL IN REPONSE TO SHORTAGE AND ITS CONSEQUENCES ON ONCOLOGY PRACTICES ACROSS THE UNITED STATES.
The Generic version is manufactured by SUN PHARMA GLOBAL FZE.
Shortage was first believed to be a commercial ploy to increase the price until it became real.   This approval will limit chances of new shortage and will help patients with Myeloma, Kaposi sarcoma and Ovarian Cancers who need this medication the most.

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!

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.

Sons of the Sevenless

SONS OF THE SEVENLESS/Hypothesis for cancer Research

As we move forward here at CRBCM, we are increasingy  fond of one line of molecules;
first because of their name, and because we believe that their inhibitors could be the answer to the resistance
to some of the medications already in our armamentarium, namely Avastin,  Imatinib and Herceptin.  We believe that the Sons of The Sevenless which are regulator molecules switching on RAS would break resistance to Tyrosine Kinase resistance.  Sons of the Sevenless, what a name!  But don't you remember they say: "KILL THE SWITCH" AND DARK WILL COME.   THE SWITCH IS THE SONS OF THE SEVENLESS...BASAL CELL CANCER OF THE BREAST, THE CRBCM IS AFTER YOU...SINCE THE SUGGESTION THAT BASAL CELL CANCER OF THE BREAST IS LIKE OVARIAN CANCER BY ITS GENOME.  MARK MY WORD: KILLING THE SONS OF THE SEVENLESS OR KILLING THE SWITCH IS THE KEY TO TREATMENT.

ADDING TAXANE (or better yet an Anti-Kinesin) AFTER KILLING THE SWITCH (SONS OF THE SEVENLESS) WILL TURN ON THE MITOCHONDRIAL CASPASE BY AN INHERENT REFLEX MECHANISM WHICH WILL BYPASS BCL-2.  THAT'S HOW YOU LEAD TO CANCER CURE!

OH BY THE WAY,  ADDING STELAZINE TO AVASTIN MAY JUST DO THE TRICK FOR RECURRENT BRAIN TUMORS TOO. IT IS AN ANTI-CALMODULIN AFTER ALL!

RESEARCH IS ON AT CRBCM.