At the CRBCM, we keep learning continously!

CONTINUING MEDICAL EDUCATION CERTIFICATE

certifies that

Mutombo Kankonde, MD
2400 Trawood Drive
Suite 303
El Paso, TX 79936

has participated in the enduring material titled

Mechanisms and Actions of HER2-Targeting Agents in Breast Cancer

April 1, 2013

and is awarded 0.50  AMA PRA Category 1 Credit(s)™.

Medscape, LLC designates this enduring material for a maximum of 0.50 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Medscape, LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

For information on applicability and acceptance of continuing education credit for this activity, please consult your professional licensing board.

Certificate Number: 42523061

Cyndi Grimes Director, Continuing Medical Education Medscape, LLC

 ==============================================================
Options to Her2 positive tumors after Herceptin!
T-DM1
pertuzumab
lapatinib +Xeloda
combination with Everolimus Neratinib

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CANCER CELLS AND THE CURE

A living cell is in constant motion. At any given time, there are periods of chemical reactions unfolding in a living cell. These processes are occurring 24/7. Despite their large number, they are not random, but are coordinated and purposeful. They have one overall objective which is the survival of the cell against all odds. However, when they cannot preserve life, they initiate the programmed cellular death. 
These cellular reactions respect basic chemical laws of ion and atom interactions. However, the general direction from reactions is imposed by the cellular mission which is clearly determined by the location of the cell in a tissue or organ and the expected function to be performed by the organ. At any given point in time, the cell is either in differentiation or proliferation, or changing to adapt to current circumstances of the cell. These functions and adaptations are caused by environmental stimuli reaching the cell.
 These stimuli could be chemical, hormonal, traumatic or electric and they reach receptors which cross the cellular boundaries or membrane, and affect the molecules belonging to a signal transduction pathway. The signal goes on to affect genes in the nucleus of the cell where DNA will be replicated to achieve or respond to the stimuli accordingly. All reactions follow a certain flow to achieve a purpose for the cell. To control the general direction of reaction the cell uses several methods: the first is to silence un-needed genes and to amplify the expression of needed genes that carry the code for the mission to be performed. 
The cell will enter division and proliferation of those genes to impose the general direction or flow of the reaction. The second method used to impose the general direction is the formation of genes that can catalyze or force the reaction to go a certain way: these are called "enzymes" for that particular reaction. If an enzyme is not formed, the reaction is not allowed to progress. Therefore, the control of what is happening is occurring this way. A third way to control the flow of direction is to promote proteins called "regulators". The more the regulators in a reaction, the more likely that regulated reaction can occur in a controlled fashion. The fourth way of controlling reaction is mole fraction which puts together certain regulators and enzymes or proteins in general which are aligned in a chain and forces molecules to go from one protein to another in the mole in a certain direction so that the output is what is needed for the mission. 
These mole-like complexes of proteins are called "core binding factors". Any protein function not needed will not be incorporated in the complex. Genes are silenced by methylation, or simply by being attached to patches of molecules that belong to the histones, the histones that cover genetic material. At any given point, when a gene is needed, the cover can be re-opened or pulled back, which is called "gene remodeling". A cancer cell will tend to move away from the location where it is located not because of its intention to kill the host, but because in that location the nutrients and local conditions will be inadequate eventually to allow further growth. It will seek another location to survive. Before it moves away, it has to take steps to protect its survival. It will break adhesion to surrounding cells; this is mostly achieved by decreasing its surface adhesion molecules. It will secrete proteins that can break fibers on its way in order to get through and detection of these proteins called “metalloproteases” can signal doctors that the disease, the cancer, is on the move. In certain circumstances, it produces a mucus to protect itself against detection by the immune system. 
When it arrives in the new location, the cell will produce a hormone or growth factor which gives itself advantage over the already present cells in that location. This is generally called a “tumor growth factor”. The potential for proliferation, division and growth advantage is driven through the signal transduction pathway inside the cell. This is generally achieved by the expression of a driver gene which is amplified or over-expressed forcing reaction for downstream pathways. This is called a “driver mutation”. 
Experience with chemotherapy which was like a bomb with an indiscriminate effect affecting both good and bad cells of the host has only been able to achieve 20 to 30% of cure. Today, scientists are targeting the driver mutations to stop pathways of growth of cancer cells. We are now getting higher response rates and starting to see response in cancers that were resistant to chemotherapy, e.g. melanoma. People used to talk about cure without believing in their own statement, but with the advance of target therapy, cure is a real possibility. We are just at the beginning of our understanding of the various targets. Cure will be achieved.

PTGS2 & MSR1

PTGS2:
The very existence of the amplification of this gene attests to the fact that in Esophageal cancer the stress imposed by chemical and traumatic irritants will involve inflammatory pathways and over-expression of Cyclins and growth Factors. Over-expression of COX-2 that this gene amplification represents leads to the formation of prostaglandins which decrease membrane protection by PGH2 and PGI2, with ulceration at the tumor level resulting. When you see an ulcerated cancer in the stomach or at the base of the Esophagus, you understand what happened!
It points to the potential importance of Interferon treatment as an adjunct therapy.

MSR1  (Macrophage Scavanger Receptor 1):
This gene amplification may stop Macrophages from removing irritated and altered cancer cells,. Irritated neoplastic cells often contain HSP (Heat shock proteins) altered proteins that should trigger action by the scavenger.  But Mutation at MRS1 leads to a tolerance of the existence of these neoplastic cells.  The HSP are normally generated by HSPA1A, a gene " located in the major histocompatibility complex class III region, in a cluster with two closely related genes which encode similar proteins."<sup>(wikipedia) 

In a normal cell, HSP will interact with ASK1 (Apoptosis  Signal-Regulating Kinase1)  and trigger independently Apoptosis, or use the same molecule as MAP3K5 to stimulate c-JUN (the stress pathway).  And don't tell me we didn't warn you that, in the pathogenesis of Esophageal cancers, irritants will stimulate C-JUN the stress related family member of the MAP Kinases.  ASK1 interacts with TNF alpha Receptor and a bunch of DNA protein Kinases that will lead to the production of inflammatory factors including the Autoimmune Antigen Ku! 
There you have it, do not be surprised that HSP has much to do with other altered proteins called Amyloids...and you start getting the right idea that Alzheimer's disease is around the corner!  Yes, the tolerance induced by Mutated MSR1 and HSP has something to do with the disposition of Amyloid deposits!</sup>

Esophageal Cancer (continued)

We have discussed that chemical, traumatic and sometimes burns from caustic solutions that people ingest unfortunately, that will stimulate the cellular membrane receptors which in turn will stimulate RAS, which in turn will amplify PI3K, MAP Kinase and RAL/CDC42.   But remember these are stressful stimulations, so instead of the standard MAPK, the stimulation is imposing on RAS to awake the NFkB pathway, the c_JUN and at nuclear level the FOS which results in inflammatory proteins stimulation including cyclin production or liberation from membranes with extracellular release of Metalloproteases. Cyclins combining to CDCs will exacerbate cell divisions and proliferation, growth factors will promote cell growth, there is an associated ligase proliferation that will impact P53 (through MDM2) and  c-MYC, NOTCH, and even c_JUN itself through FBW7/hCDC4.  This is how the proteasomes come into play!

By now you now
1. that amplification of c-MYC exacerbate proliferation by allowing progression of cells int S-phase and bolster DNA replication, imparting bad prognosis to cancer cells.
(nature is kind and gies you a chance to affect here by freeing RB1 and increasing FBW7.  Oh! also find MYCN and the p isoform to q for answers!)

2 Rb1 does sequester E2F.   you can look at it both ways.  that E2F stabilize Rb1 instead,  whichever way one stop the other for acting!   Remember E2F activates CPP32 which increase APOPTOSIS!  (DRUM UP THOSE TARGET THERAPY!)

3.REMEMBER RAS NEEDS A FATTY ACID MOIETY TO STAY AT THE MEMBRANE FOR ITS ACTIVITY (THIS IS ITS SO CALLED POST-TRANSLATIONAL MODIFICATION) BY THIS PHRENYLATION IS IMPAIRED BY THE FARNESYL TRANSFERASE INHIBITOR
(ie. TIPIFARNIB) THAT WE DO NOT USE ENOUGH I FEEL!  ALTHOUGH I AGREE THAT SIDE EFFECTS MAY BE PROHIBITIVE GIVEN THE EXTENT OF WHICH NORMAL CELLS WILL ALSO BE COMPROMISED.  BUT IT GOES TO THE FACT THAT WE NEED TO FURTHER TWEAK THIS MODALITY TO MAKE IT USABLE IN CANCERS!
ANTI-MEK HAVE DEMONSTRATED USE IN KRAS MUTATION CANCERS!  MAY BE ESOPHAGEAL CANCERS WILL BENEFIT HERE!

4Role of combining Velcade and Carfilzomib in Esophageal cancer to see if c-Myc can be affected?   Will it increase the right Ligand (FBW7)?

ESOPHAGEAL CANCER
Whether you consider Adenocarcinoma or squamous cell cancer of the Esophagus, you will have to come to the realization that you are looking at the result of a chronic irritation on Esophageal mucosa.  The irritation in chemical when it comes to Gastric Acid for the Adenocarcinoma of the Gastro-esophageal (G-E) junction, or it could be traumatic as rough  stuffs are swallowed, this include chemicals and alcohols (these days you cannot imagine what people put in their mouth-live scorpions even!)   So chemical and rough stuff induce a squamous cell cancer in the upper Esophagus while Gastric reflux lead to an An Adenocarcinoma.   However you get their the insult will be register at cell level through our membrane receptors which are trans-membrane structures.  In some of these receptors, there is portion facing the cytoplasm called RTK (receptor Tyrosine Kinase) which dimerize on stimulation and/or autophosphorylate, , and   This commotion attracts the Sons of the Sevenless which lights up the RAS by bringing in the Erb2 to attach to he RTK. My sons of the Sevenless gives off a Guanine that activates RAS.    And here we go with Ras and related molecule amplifications.  RAS is known to amplify 3 pathways
1. the MAP Kinase pathways which will go on to stimulate formation of transcription factors that will make proteins structures to deal with the situation, or tell the cell what directions things will go or manage the challenge globally!
2. the RAL/CDC42 pathways that send message to the Cytoskeleton (the nervous system at cell level)
we are talking about stand up and fight Vs flight management.  This system by following the Actininic cytoskeleton through the mambrane and the Reticulum endothelium (RE) reaches in a flash the Nucleus (that's where RE goes )  We are talking in a flash the cell is informed at Histone level and is ready to process the info and react!
3. The PI3K pathways which readies the cellular response which include needed protein response but also include initiating programmed death if that is an appropriate response!  (The FOX (o) is hidden behind the MTOR down this pathway!  FOXO hold the key to survival of the cell!

REMEMBER RAS CAN NOT GO WILD EXCITING THESE PATHWAYS, IT IS TEMPERED BY NF1 WHICH BELONG TO THE FAMILY OF GAP, GIVING A GAP (BREAK) OF FUNCTION TO RAS .  IF THERE IS NO GAP, AND RAS GOES WILD, YOU GOT YOURSELF A NEUROFIBROMATOSIS ON YOUR HAND TO DEAL WITH!  IT IS WORTH NOTING THAT GAP CAN BE DECREASED RELATIVELY TO GEF.  THAT IS TO MUCH GEF IS TRANSLATED AS A DECREASED GAP AS GEF TAKES CONTROL.  SO ONE WAY TO AFFECT RAS IS TO INCREASE GEF (THE BALANCE WILL BE BROKEN TO THE DISADVANTAGE OF GAP) AND RAS WILL BE HYPERSTIMULATED! (TARGET THERAPY)

AFTER THIS VERIFICATION OF THE NOTION THAT THINGS START SIMPLY BUT GET OUT OF HAND QUICKLY IN CELLULAR METABOLISM, LETS GO BACK TO ESOPHAGEAL CANCER AND PATHWAYS STIMULATION.

(WILL CONTINUE)

DISCUSSING GENES IN ESOPHAGEAL CANCERS

* Esophageal cancers varies by types, and types are related to location
with the squamous cell cancer involving most of the upper 2 thirds of the Esophagus. It is this cancer that is linked to patients who are black, to Achalasia, caustic injury, Plummer -Vinson disease smoking and excessive alcohol consumption and to HPV.  Adenocarcinoma are linked to GERD, Barrettt Esophagus, white race, smoking and obesity.  It is also characteriZed by Metaplasia and Barett morphology

 (to be continued)


Genes in esophageal cancers

Mutation of Rb1
and overexpression of Cyclin D1
MSR1, ASCC1, and CTHRC1
CDK4 and CDK6

RHBDF2 gene      EGFR   MET    DLEC1

 PTGS2      FEZ1      DMBT1    p16       p14

ODC1      CDK4     CDK6     CD9      E2F

SPARC     p33   p53       Rb1     SLP1     c-MYC

 NK4    HGF     MDM2     PPRP         UPRT         p21WAF1       CIP

New Medications in Refractory Myeloma

After failure of Revlimid, Velcade and Dexamethasone
particularly in Del 17 patient

4 options:
1. Elotuzumab + Revlimid + Dex
2. Elotuzumab + Velcade + Dex
3. Carfilzomib +Dex
4.Pomalidomid + Velcade + Dex

Newer options
- ARRY-520 +/- Low dose Revlimid +Dex
-DARATUMUMAB
-ANTI - CD 38 MONOCLONAL ANTIBODY.

NEW COMBINATION : REVLIMID+THALIDOMID +dex  IN BAD PROGNOSIS PATIENTS

BREAKING NEWS: New CPRIT Oversight Committee Proposals Kill Commercialization Arm Of Organization

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Posted Friday , March 15,2013 from www.statesman.com › Business

A set of newly-published proposals put forth by the CPRIT oversight committee strips out the Chief Commercialization Officer and related committees, suggesting that the cancer fighting organization will no longer be permitted to attract new biotech companies into Texas.
A sweeping set of new proposals posted today on the Texas Register by the CPRIT oversight committee seeks to make wide-ranging changes to the cancer research funding organization by effectively eliminating its role in using Texas taxpayer dollars to foster biotech startups in the state, as well as attract major biotech corporations to relocate. The new statues, which propose changes to virtually every aspect of the organization, appears to replace the entire commercialization arm with new compliance and oversight officers, as represented in Section 703.2 of the document:

Section 703.2 adds the definitions for “chief product development officer”, “compliance officer”, “product development review council”, and “product development prospects.” The section proposes to delete references to the “chief commercialization officer”, the “commercialization review council”, and “commercial prospects”. The section also clarifies the definition of “cancer research” to include research into the prevention of cancer.

Deleting references to the “chief commercialization officer,” “commercialization review council,” and “commercial prospects,” suggests that CPRIT’s new organizational structure will not include its once robust operations to attract private biotech companies into the state. These changes would lay to waste incubator programs designed to help foster new start-ups within Texas, as well as significant relocations of biotech operations.
Conversely, the addition of roles such as “chief product development officer,” “product development review council,” and “product development prospects” would suggest that the commercialization arm will now be more limited in scope, and focus on smaller, in-state product development projects, rather than attracting entire business and operations into the state. The new document describes the role of chief product development officer as: “. . . the individual employed by the Institute to oversee the review and evaluation of grant applications for the development of drugs, biological, diagnostics, or devices arising from cancer research and prevention activities.”

Similarly, the designation of product development prospects is described as: “the potential for development of products, services, or infrastructure to support cancer research efforts, including but not limited to pre-clinical, clinical, manufacturing, and scale up activities.”
It is particularly interesting that this section juxtaposes the deletion of CPRIT’s commercialization arm with the addition of a compliance officer — a detail that only further suggests that these proposals constitute a sea change in the scope and direction that CPRIT will take in the foreseeable future, should these proposals be passed by the Texas legislature.
Download a .pdf of the CPRIT Oversight Committee’s proposed amendments.
Be sure to subscribe to BioNews Texas and receive instant notifications of updates to the CPRIT story and more!
Let us know in the comment section below what you think of this proposed change to the way that CPRIT operates.

Related News Articles:

• Former CPRIT Chief Science Officer Gilman Elected Inaugural Fellow of the American Association for Cancer Research
• EXCLUSIVE: CPRIT Proposes Creation of New “Product Development Officer” To Replace Commercialization

WHEN YOU THINK ABOUT IT
GASTRIC CANCER, PARTICULARLY THAT IS FROM THE GE JUNCTION, IS A DISEASE INDUCED BY GASTRIC ACID IRRITATION.  NOW WE KNOW THAT C-JUN AND NF-kB , HiF, FOS AND MAY BE HSP 90 MUST BE INVOLVED.  THE RESULT IS GROWTH FACTORS, TNF AND INTERLEUKIN/INTERFERON MUST BE INVOLVED.  WE KNOW THE EGFR HAVE BEEN USED.

HOW ABOUT INTERFERON ALPHA, AND MONTELUSKA FOR THAT MATTER!WE DEFINATELY NEED TO TARGET FHIT AND BRING IN SURAMIN!

HOLD ON TO THESE THOUGHTS
==========================
1.
"Multiplex Testing in cancer may alleviate cost issue, testing fatigue, and reduce Histology discrepancies" 
(Antoinettte J. WozniaK )

I agree that by checking several genetic markers at once, one will reduce cost.   We know it cost less to do a package than individual.   the experience with Complete Metabolic panels should reproduced at Biomarkers'level.

And yes I looked at the pathologist as he was passing by, I noted he tried to avoid me because each time we meet I always ask him for another biomarker to test.  He is really tired of testing.  So the statement must be true  and the cost rising on each individual patient!

Histology discrepancies reduced? hmmmm!
This one I need to scratch my head a bit! Is that means test everybody independent of histology?  Is that wise (outside a clinical trial?)   let's think about this!  well tell me what you think!

2.  "Biomarkers for Dummies"
I don't believe there is such a book!  That's it.  How can this be...?  Can you really be a dummy if you understand what is a Biomarker!  I guess there is a trick to all this that is escaping Me!

3. I get it, don't  get to excited trying to test everybody!  These are the rates of positive test in lung cancers:

-ROS-1 positive in 1.5 % of lung cancers
-ALK positive in 5%
-RET positive in 2%
-EGFR positive in 18%
-HER-2 positive in 2%
-BRAF positive in 3%
-MET positive in 3%
The total is 35% which is meaningful only globally and a waste of time if you go one by one.   NOW I AGREE THESE SHOULD COME AS A PANEL!

More on lung cancer
*10-15% of Squamous and Adenocarcinoma will be misdiagnosed by Transbrochial biopsy (Soler et al.).
* On tissue, test TTF1 to confirm presence of Adenocarcinoma
and P63 for Squamous histology
*Definitely check for EGFR status prior to giving the first treatment because gefitinib gives consistently higher response rate and progression free survival  in various trial (NEJ002, WJTOG, OPTIMAL and EURTAC)
*Give Crizotinib if ALK positive tumor! (AT 250MG PO BID)(SAME DOSAGE WITH GEFITINIB!)
*Remember KRAS tranduce or is downstream the EGFR stimulation.
However Amplification of KRAS "may indicate lack of responsiveness to EGFR-TKI (Tyrosine Kinases Inhibitors).

ROS-1
is in close proximity to ALK
Use Crizotinib in ROS -1 positive patients

MetMAb
----------
MET amplification does give worse prognosis to cancers
MET amplification does give resistance to Gefitinib/Erlotinib

IN SECOND LINE SETTING (AFTER FAILURE OF ONE REGIMEN IN METASTATIC LUNG CANCER) TAXOTERE WAS EQUALLY EFFECTIVE TO PREMETREXED.  BUT FOR AN UNCLEAR REASON, PREMETREXED DID BETTER IN LARGE CELL CANCER TYPE.  THIS IS AN INTERESTING ISSUE.  (HANNA N ET AL. FOR ORIGINAL JCO ARTICLE).

  

S100A4, AN IMPORTANT TARGET FOR SURE! LOCATED AT 1q21

The importance of a molecule in the body is determined  by its chemical properties, the pathogenesis of the disease in which it is  participating or how critical a function it is performing in the cascade of a pathway. The importance of a gene is determined by its product's shape and function which is sometimes defined by atoms hanging at its periphery, ready for business of attracting other electrons or ions.  It is also determined by genes in a linkage relationship at the chromosome level. This last point is important to be clarified by researchers who have the tools to explore the coexistence of genes on an arm of a specific chromosome.  And a lot of research forgets to look at that aspect of the problem gene. (don't forget "q" most of the time portends for worse prognosis than "p" , that is it may induce a malignant phenotype.  In fact, co-expression of homologue "p" will mitigate the phenotype. And the homologue gene is on a p arm and on a different numbered chromosome)

By now you also know that cell life is directed in one direction at a time frequently.  Cells are under function performance, differentiation, proliferation or neoplastic transformation.  Neoplastic cells are in concert with surrounding cells from which it avoids to be in conflict with to escape detection.  Neoplastic Cells will be soon stressed because of their increased needs and through the c-JUN -FOS will increase a Tumor Growth factor liberated from the cellular membrane with concomittent release of Metalloproteases in the extracellular membrane through flippase-floppase activity.  The Metalloprotease goes out, the Growth factor goes in.
IT WOULD BE GOOD TO KNOW WHICH METALLOPROTEASE IS SPECIFICALLY LINKED TO WHICH PROTEIN IN ORDER TO KNOW WHAT IS GOING ON INSIDE THE CELL JUNK BY DETERMINING WHICH OF THE METALLOPROTEASE   FAMILY MEMBER IS IN THE EXTRACELLULAR SPACE OR BLOOD!   NICE LITTLE PROJECT RIGHT THERE.  "WHICH TYPE OF METALLOPROTEASE FOR WHICH CANCER"  I BET, BRAIN TUMOR WILL RELEASE A DIFFERENT METALLOPROTEASE THAN OVARIAN CANCER.  BECAUSE THE GROWTH HORMONE RELEASED IN THE CELL WILL BE DIFFERENT.

By now you also know that in certain proliferative processes, there is an increased aspect of only 1 or 2 functions.  In Leukemias, for example, it is amplification of a certain Core binding complex which attaches certain molecules with specific functions.  And the cell follows the cascade of functions to go in a certain cell life trend.  Some of these proteins are gene regulators.  In fact, Leukemia would be better controlled if we just determined the proteins on CBF and the regulators that are promoted in the cell.  ANOTHER EASY PROJECT : THE PATTERNS OF GENE REGULATORS IN A SPECIFIC LEUKEMIA (BY WETERN OR SOUTHERN BLOT).

One of those regulators is the S100A4, a potent regulator which not only is at the differentiation, meaning when mutated or amplified it will create phenotypic havoc for sure.  It is handling Calcium, therefore will affect some Microtubules (good or bad for Taxanes?):  Time to find out more! Read these articles!

1. High expression of S100A4 in cytoplasm at the advancing front of stage C colonic tumours indicates a poor prognosis.
2. The S100A4 protein, mostly studied in cancer, is overexpressed in the damaged human and rodent brain and released from stressed astrocytes.
3. we show for the first time the intratumoral knock down of S100A4 via systemic application of S100A4shRNA plasmid DNA, restricts metastasis formation in a xenografted mouse model of colorectal cancer.
4. SRX forms a complex with S100A4 (and has stronger affinity for S-glutathionylated S100A4), regulates its activity, and mediates redox regulation of the interaction of S100A4 with nonmuscle myosin heavy chain II-A.
5. S100A4 and its downstream factors play important roles in pancreatic cancer invasion, and silencing A100A4 can significantly contain the invasiveness of pancreatic cancer.
6. HBXIP up-regulates S100A4 through activating S100A4 promoter involving STAT4 and inducing PTEN/PI3K/AKT signaling to promote growth and migration of breast cancer cells.
7. S100A4 and VEGF mRNA levels were up-regulated in clear cell renal cell carcinoma (CCRCC), tissue compared with control; upregulated tumour S100A4 and VEGF mRNA levels were independent risk factors for the presence of invasion and/or metastasis
8. High S100A4 is associated with ovarian cancer invasiveness.
9. FSP1 localized to podocytes in focal segmental glomerulosclerosis & minimal change disease. The number of FSP1(+) podocytes per glomerular profile was higher in patients with FSGS than in MCD. There was a corresponding difference in FSP1 mRNA levels.
10. Asymmetric mode of Ca-S100A4 interaction with nonmuscle myosin IIA generates nanomolar affinity required for filament remodeling in epithelial carcinoma cells.

NOTE HBXIP S100A4:  AN IMPORTANT TARGET FOR CERTAIN!

From the Microbial World

Some clinically important antibiotics
Antibiotic	Producer organism	Activity	Site or mode of action
Penicillin	Penicillium chrysogenum	Gram-positive bacteria	Wall synthesis
Cephalosporin	Cephalosporium acremonium	Broad spectrum	Wall synthesis
Griseofulvin	Penicillium griseofulvum	Dermatophytic fungi	Microtubules
Bacitracin	Bacillus subtilis	Gram-positive bacteria	Wall synthesis
Polymyxin B	Bacillus polymyxa	Gram-negative bacteria	Cell membrane
Amphotericin B	Streptomyces nodosus	Fungi	Cell membrane
Erythromycin	Streptomyces erythreus	Gram-positive bacteria	Protein synthesis
Neomycin	Streptomyces fradiae	Broad spectrum	Protein synthesis
Streptomycin	Streptomyces griseus	Gram-negative bacteria	Protein synthesis
Tetracycline	Streptomyces rimosus	Broad spectrum	Protein synthesis
Vancomycin	Streptomyces orientalis	Gram-positive bacteria	Protein synthesis
Gentamicin	Micromonospora purpurea	Broad spectrum	Protein synthesis
Rifamycin	Streptomyces mediterranei	Tuberculosis	Protein synthesis

Antibiotics are the new "old frontier " for target therapy for cancer treatment
and I am not talking of cell wall  agents,  but  agents that target miRNA.  Griseofulvin targets Microtubules but there is a different in nature of microtubules that makes it ineffective for human. It may need some tweaking. Anti ribosomal drugs (80s) may also be of interest.

Go ahead and look into these

1. Polymyxin
2. Rifamycin
3. Avenacin
4. Cinnamic Acid
5. Phtalic Acid 
6. Suramin  ie.
----------------------
NCI
" Suramin 

A polysulphonated naphthylurea with potential antineoplastic activity. Suramin blocks the binding of various growth factors, including insulin-like growth factor I (IGF-I), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and tumor growth factor-beta (TGF-beta), to their receptors, thereby inhibiting endothelial cell proliferation and migration. This agent also inhibits vascular endothelial growth factor (VEGF)- and basic fibroblast growth factor (bFGF)-induced angiogenesis; retroviral reverse transcriptase; uncoupling of G-proteins from receptors; topoisomerases; cellular folate transport; and steroidogenesis. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)'"

LOX Lysyl-Oxidase

This gene found in gastric and bladder cancer is prognostic.  Its amplification allows the cell to deal with austere conditions in Metastatic conditions.  It seems to be amplifying under the impetus of HIF (Hypoxia induced factor). Its amplification appears more reactive than driving the resulting dowstream reaction.It can affect the structure of laminin and collagen through its formation of Aldehyde.
It can push proliferation by acting as a co-factor at nuclear level.
It can affect AKT (Protein Kinase B).
Recently, a study in Sarcoma using a Doxorubicin isoform was set in motion. Expression of LOX should be included in the analysis since Hypoxia was a component of the treatment.
LOX would not be a principal target in a treatment strategy since it addresses mostly metastasis, it either an adjunct treatment, or will have a role in Maintenance therapy.

* A new study suggests that Maintenance Docetaxel increases significantly progression survival: "Single-dose monthly maintenance treatments for a total of up to 12 months were offered to patients who had a complete response. Median time to recurrence was 39.3 months in responders treated with maintenance docetaxel, compared with 19 months in those who did not receive maintenance therapy.<sup>"(Medscape)

*READ IT1</sup>

"Radiolabeled Small Molecules Show Promise in Prostate Cancer Early Detection

By Zach Hartman | March 20, 2013

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Radiolabeled small molecules targeting prostate-specific membrane antigen (PSMA) are well-tolerated tools for detection of metastatic prostate cancer, according to data published in the March 2013 issue of the Journal of Nuclear Medicine."

*Lymphoseek FDA approved for detection of metastatic disease involving the lymph nodes for Breast cancers and Melanoma!

A few Genes on Bladder Cancer

MUC1:  Mucinous cancers are known to be dangerous because by the time they are diagnosed, the extent is a little more then first thought.  Mucin is used by cancer cells to hide from immune detection it is believed.  MUC1 interacts with GrB 2 which affects a multitudes of other genes and transcription factors.Through YES1, it interacts with JAK2.  Action through JAK2 may have been why Epogen was prohibited for use in the Curable cancer setting.  JAK2 sensitizes cancer to Epogen, and to other growth factors!
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AZPG1

"Original Article

Oncogene 29, 5146-5158 (16 September 2010) | doi:10.1038/onc.2010.258

AZGP1 is a tumor suppressor in pancreatic cancer inducing mesenchymal-to-epithelial transdifferentiation by inhibiting TGF-β-mediated ERK signaling

B Kong, C W Michalski, X Hong, N Valkovskaya, S Rieder, I Abiatari, S Streit, M Erkan, I Esposito, H Friess and J Kleeff

Abstract

Epithelial-to-mesenchymal transdifferentiation (EMT) mediated by transforming growth factor-β (TGF-β) signaling leads to aggressive cancer progression. In this study, we identified zinc-α2-glycoprotein (AZGP1, ZAG) as a tumor suppressor in pancreatic ductal adenocarcinoma whose expression is lost due to histone deacetylation."
It is associated with FAT/cahchexic losses in these patients
===================================================

TMPRSS2-ERG fusion
NKX3
c-MYC
PTEN
Favorable Gene hCAP-D3
-----------------------------------------------------
In Gastric Cancer
LOX
RASSF6
MR1
miRNA 107 (DICER1)
PDCD4
-------------------------------------------------
In Colon Cancer

Annexin
S100A4
SERCA
GF15
BAX

Hypothesis of small cell cancer pathogenesis

Hypothesis of small cell cancer pathogenesis
It seems that stimulation from smoking and stress acting through the FOS /c-JUNK will hit at nuclear level, genes of differentiation such FHIT,( The gene encompasses the common fragile site FRA3B on chromosome 3, where carcinogen-induced damage can lead to translocations and aberrant transcripts of this gene. In fact, aberrant transcripts from this gene have been found in about half of all esophageal, stomach, and colon carcinomas.

^It also known as human accelerated region 10.)  (wikipedia)
FHIT will in turn affect UBE2I, the SUMO-conjugating enzyme altering this way ubiquitination
But UBE1I also affect a Myriad of important genes that will start and amplify the neoplastic process:
UBE2I has been shown to interact with WT1,^[3] TOP1,^[4] RAD51,^[5][6] Activating transcription factor 2,^[7] PIAS1,^[8][9][10] SALL1,^[11] FHIT,^[12] RANBP2,^[13][14] Protein inhibitor of activated STAT2,^[8][15] DNMT3A,^[16] DNMT3B,^[17] Small ubiquitin-related modifier 1,^{[6][13][18][19]} SAE2,^[13][20] RANGAP1,^[13][18][20] Death associated protein 6,^[20][21] Androgen receptor,^[22] ETS1,^[23] IPO13,^[24] TCF3,^[25] TNFRSF1A,^[26] DACH1,^[15][27] P53,^{[6][19][28][29]} BLMH,^[30] MAP3K1^[26] and Microphthalmia-associated transcription factor.^{[31] (wikipedia)}

Top 1 and Rad1: these affects BRCA and other genes of DNA repair including P53.  The neoplastic process wants tolerance of gene abnormalities in neoplastic cells.  Methylation of FHIT is critical for cancer to mature!

also...

GENES HYPERMETHYLATED TO FAVOR DEDIFFERENTIATION, AND NEOPLASTIC TRANSFORMATION IN LUNG CANCERS

RESEARCHERS SUGGEST THE FOLLOWING GENE AS TARGET FOR HYPERMETHYLATION: 1. DAPK

DAPK1

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Death-associated protein kinase 1
PDB rendering based on 1ig1.
Available structures PDB Ortholog search: PDBe, RCSB [show]List of PDB id codes
Identifiers
Symbols	DAPK1; DAPK
External IDs	OMIM: 600831 MGI: 1916885 HomoloGene: 3626 ChEMBL: 2558 GeneCards: DAPK1 Gene
EC number	2.7.11.1
[show]Gene Ontology
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1612	69635
Ensembl	ENSG00000196730	ENSMUSG00000021559
UniProt	P53355	Q80YE7
RefSeq (mRNA)	NM_004938	NM_029653
RefSeq (protein)	NP_004929	NP_083929
Location (UCSC)	Chr 9: 90.11 – 90.32 Mb	Chr 13: 60.6 – 60.76 Mb
PubMed search	[1]	[2]

Death-associated protein kinase 1 is an enzyme that in humans is encoded by the DAPK1 gene.^[1]
Death-associated protein kinase 1 is a positive mediator of gamma-interferon induced programmed cell death. DAPK1 encodes a structurally unique 160-kD calmodulin dependent serine-threonine kinase that carries 8 ankyrin repeats and 2 putative P-loop consensus sites. It is a tumor suppressor candidate.^[2]
In melanocytic cells DAPK1 gene expression may be regulated by MITF.<sup>[3]"

AND YOU KNOW THAT ANYONE WHO WANTS TO LIVE WILL SILENCE THIS GENE.  KILLING INTERFERON EFFECT IN LUNG CANCER DESPITE STRESS INDUCTION ROLE IN THE PATHOGENESIS OF LUNG CANCERS.
-------------------------------------------------------------------THIS GENE WAS DISCUSSED IN OTHER BLOG NOTE---------</sup>

2. GSTP1

GSTP1

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Glutathione S-transferase pi 1
PDB rendering based on 10gs.
Available structures PDB Ortholog search: PDBe, RCSB [show]List of PDB id codes
Identifiers
Symbols	GSTP1; DFN7; FAEES3; GST3; GSTP; PI
External IDs	OMIM: 134660 MGI: 95864 HomoloGene: 660 ChEMBL: 3902 GeneCards: GSTP1 Gene
EC number	2.5.1.18
[show]Gene Ontology
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	2950	14869
Ensembl	ENSG00000084207	ENSMUSG00000038155
UniProt	P09211	P46425
RefSeq (mRNA)	NM_000852	NM_181796
RefSeq (protein)	NP_000843	NP_861461
Location (UCSC)	Chr 11: 67.35 – 67.35 Mb	Chr 19: 4.04 – 4.04 Mb
PubMed search	[1]	[2]

Glutathione S-transferase P is an enzyme that in humans is encoded by the GSTP1 gene.^[1][2]
Glutathione S-transferases (GSTs) are a family of enzymes that play an important role in detoxification by catalyzing the conjugation of many hydrophobic and electrophilic compounds with reduced glutathione. Based on their biochemical, immunologic, and structural properties, the soluble GSTs are categorized into 4 main classes: alpha, mu, pi, and theta. The glutathione S-transferase pi gene (GSTP1) is a polymorphic gene encoding active, functionally different GSTP1 variant proteins that are thought to function in xenobiotic metabolism and play a role in susceptibility to cancer, and other diseases.^[3]
GSTP1 has been shown to interact with Fanconi anemia, complementation group C^[4][5] and MAPK8.<sup>[6]"

METHYLATION HERE IS TO PERPETUATE THE ACTION OF CAUSING FACTORS.  IT IS BAD FOR PATIENTS TO CONTINUE SMOKING ON TREATMENT.  THIS IS AN EARLY EVENT IN TUMOR NEOPLASIA TRANSFORMATION.</sup>

Cyclic AMP mediated GSTP1 gene activation in tumor cells involves the interaction of activated CREB-1 with the GSTP1 CRE: a novel mechanism of cellular GSTP1 gene regulation.

Lo HW, Ali-Osman F.

PUTING THE EFFECT DEEP INTO THE MITOCHNDRIA.  WHERE THE MTOR INHIBITORS WORK?

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3.RAR BETA:This gene encodes retinoic acid receptor beta, a member of the thyroid-steroid hormone receptor superfamily of nuclear transcriptional regulators. This receptor localizes to the cytoplasm and to subnuclear compartments. It binds retinoic acid, the biologically active form of vitamin A which mediates cellular signalling in embryonic morphogenesis, cell growth and differentiation. It is thought that this protein limits growth of many cell types by regulating gene expression. The gene was first identified in a hepatocellular carcinoma where it flanks a hepatitis B virus integration site. The gene expresses at least two transcript variants; one additional transcript has been described, but its full length nature has not been determined.

EXPLAINING WHY RETINIOIC ACID (PREVENTION) AND ATRA MAY NOT WORK FULLY!

4.ECAD
5.p14 ARF
6.p16
7.TIMP1
8.FHIT

THEY WILL NOT LET US DO THIS WORK UNFORTUNATELY AT FULL POTENTIAL BECAUSE WE ARE NOT ASIANS OR CONNECTED WITH ACADEMIA,  BUT WE WILL CONTINUE THE WORK WITHIN OUR MEANS BECAUSE THE TIME HAS COME!  WE WILL DIE SAYING SOMETHING!
CURE IS NOT FAR, WHAT MAKES IT FAR IS POLITICS (SUCH AS CPRIT), THE SYSTEM WHICH IS BIASED TOWARD UNIVERSITIES, AND BUILT-IN FALLACY (REVIEWERS COME FROM ONE BACKGROUND AND RATE PROPOSALS NOT ON SCIENTIFIC MERIT, BUT BASED ON THEIR KNOWLEDGE OF RESEARCHERS OR PRESUMPTIONS - "HE IS NOT ASIAN, THEREFORE HE CAN'T DELIVER".)  WE ARE GOING TO PROGRESS WITHOUT THEM.  WE ASK THAT EVERYWHERE YOU ARE, USE THE INFORMATION YOU FIND ON THIS BLOG FREELY AND LET THE BEST CONNECTED WIN!
THERE IS AN ASIAN RESEARCHER WHO WAS BROUGHT INTO CPRIT AND MANAGED TO SECURE A GRANT FOR HER HUSBAND, AND SHE GOT AWAY WITH IT BECAUSE SHE IS ASIAN AND IN THIS FIELD ASIANS ARE GETTING A PASS, THEY CAN TRULY GET AWAY WITH ANYTHING!  IF YOU ARE ASIAN, TAKE A NOTE, APPLY TO CPRIT...GUESS WHO FROM MD ANDERSON SPOKE ABOUT BEING PROUD OF THE NEW RELEASE OF FUNDS, ANOTHER ASIAN RESEARCHER!  IF YOU ARE A RESEARCHER FROM ASIA, CONTACT US, WE WILL HIRE YOU WITH CPRIT FUNDING! CALL 915-307-3354.

IN SMALL CELL LUNG CANCER ONE CANNOT OVER-EMPHASIZE THE ROLE OF SOX2 GENE!

IT IS A GENE THAT LEADS TO ORGAN DEVELOPMENT (EYES), ANOPHTHALMIA SYNDROME, MICROPHTHALMIA, SEPTO-OPTIC DYSPLASIA
 LOCATION 3q26  (NOTE THE Q)
IF IT INVOLVES ORGAN DEVELOPMENT, REMEMBER THALIDOMID AND ANTI-ANGIOGENIC DRUGS EFFECT!

SOX2

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SRY (sex determining region Y)-box 2
PDB rendering based on 1gt0.
Available structures PDB Ortholog search: PDBe, RCSB [show]List of PDB id codes
Identifiers
Symbols	SOX2; ANOP3; MCOPS3
External IDs	OMIM: 184429 MGI: 98364 HomoloGene: 68298 GeneCards: SOX2 Gene
[show]Gene Ontology
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	6657	20674
Ensembl	ENSG00000181449	ENSMUSG00000074637
UniProt	P48431	P48432
RefSeq (mRNA)	NM_003106	NM_011443
RefSeq (protein)	NP_003097	NP_035573
Location (UCSC)	Chr 3: 181.43 – 181.43 Mb	Chr 3: 34.65 – 34.65 Mb
PubMed search	[1]	[2]
This box: view talk edit

SRY (sex determining region Y)-box 2, also known as SOX2, is a transcription factor that is essential for maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells. Sox2 is a member of the Sox family of transcription factors, which have been shown to play key roles in many stages of mammalian development. This protein family shares highly conserved DNA binding domains known as HMG (High-mobility group) box domains containing approximately 80 amino acids. Sox2 has a critical role in maintenance of embryonic and neural stem cells and holds great promise in research involving induced pluripotency, an emerging and very promising field of regenerative medicine.^[1]

Contents 1 Function and expression in pluripotency 2 Role in neural stem cells 3 Interactions 4 Clinical significance 5 Eye deformities 5.1 Cancer 6 References 7 Further reading 8 External links

Function and expression in pluripotency

LIF (Leukemia inhibitory factor) signaling, which maintains pluripotency in mouse embryonic stem cells, activates Sox2 downstream of the JAK-STAT signaling pathway and subsequent activation of Klf4 (a member of the family of Kruppel-like factors). Oct-4, Sox2 and Nanog positively regulate transcription of all pluripotency circuitry proteins in the LIF pathway.^[2]In an experiment involving mouse embryonic stem cells, it was discovered that Sox2 in conjunction with Oct4, c-Myc and Klf4 were sufficient for producing induced pluripotent stem cells.^[6] The discovery that expression of only four transcription factors was necessary to induce pluripotency allowed future regenerative medicine research to be conducted considering minor manipulations.
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Its association with NM1  increase its amplification.
Here you find the role of JAK-STAT pathway as prominent in SCLC.
You also find understand why this propensity to CNS metastasis
They did not say anything about MEK, the door to dedifferentiation!
It forms a complex with OCT4
and interacts with  YES1, FGF4, UTF1 and ZFP206 (By similarity)
and with  . Downstream

SRRT target that mediates the promotion of neural stem cell self-renewal (By similarity). Keeps neural cells undifferentiated by counteracting the activity of proneural proteins and suppresses neuronal differentiation (By similarity)

Subunit: Interacts with ZSCAN10 (By similarity). Interacts with SOX3 and FGFR1 (By similarity) Subcellular location: Nucleus Biotechnology: POU5F1/OCT4, SOX2, MYC/c-Myc and KLF4 are the four Yamanaka factors.

 
--------------------------------------------------------------This gene lies within an intron of another gene called SOX2 overlapping transcript (SOX2OT). The importance of SOX2 and OCT4 as regulators of pluripotency has been dramatically illustrated by the demonstration that these factors together with c-Myc and Klf4 or Nanog and LIN28 can induce the dedifferentiation of somatic cells into induced pluripotent stem cells (iPS) with many of the features of embryonic stem cells, Takahashi, K. and Yamanaka, S. (2006); Wernig, M. et al. (2007) and Yu, J. et al. (2007).

  Nanog is also a very important early regulator of pluripotency. Together SOX2, OCT4 and Nanog co-regulate a growing list of downstream target genes. Target genes include YES1, FGF4, UTF1, Fbx15, Zic3 and ZFP206, but this is only a sampling of the hundreds of genes that are involved. The targets of SOX2, OCT4 and Nanog have recently been identified using time course microarray and genome-wide immunoprecipition data, Sharov, A.A, et al. (2008).
Loss of function SOX2 mutations have been linked to the rare disease microphthalmia syndrome type 3, small eye, (MCOPS3), Ragge NK, et al. (2005); Verma, A.S, and Fitzpatrick, D.R. (2007.)
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(Chen et al.) SOX2 contributes to the tumorigenesis of lung cancer cells and can be used as a diagnostic probe. In addition, obviously higher expression of oncogenes c-MYC, WNT1, WNT2, and NOTCH1,  AND YOU KNOW THAT IF YOU TOUCH THE WNT , YOU FIGHT VIGOROUSLY BREAST CANCER!  OPENING UP SOX2 AS A MAJOR TARGET IN BREAST AND LUNG CANCERS!
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IF YOU DO NOT FIND A TARGET THERAPY, DREAM AGAIN!
REMEMBER THIS WHERE ANTI-HISTONE DEACYL TRANSFERASE INHIBITOR COMES HANDY!  AND YOU GUESSED IT, SOME ANTIBIOTIC FROM FUNGI WHICH ATTACK TRANSCRIPTION FACTORS.