THE PROOF IS IN THE PUDDING, WE HYPOTHESIZED THAT TRIPLE NEGATIVE BREAST CANCER RESULTED FROM THE FAILURE OR DEFICIENCY IN PROTEOGLYCAN HEPARAN SULFATE FROM CONGENITAL REASON OR AN IMMUNE DEFICIENCY,  THIS UNFORTUNATELY LEADS TO A RELATIVE RESISTANCE OF ESTROGEN RECEPTORS TO TUMOR GROWTH FACTOR BETA..==========================================
============================

Like any other resistance to conquer, the cell will increase the relative secretion of TGF beta with devastating consequences!  While failing to efficiently stimulate the Estrogen receptor, through SP1, TGF-BETA will stimulate the Aryl Hydrocarbon receptor which is normally "dormant" in the cytosol, stimulation of AHR not only renders the cell susceptible to

natural plant flavonoids, polyphenolics and indoles, as well as synthetic polycyclic aromatic hydrocarbons and dioxin-like compounds. AhR is a cytosolic transcription factor that is normally inactive,(see references)

but the increase of TGF induced Sp1 activity wakes this receptor up!

but also this receptor through ARNT, will induce the expression of genes such as Hsp90 (the stress gene--waking up the NF-kB), CYP (the modulator of estrogen and other ) but also all the genes interacting with Sp1,  including 

RELA,^[66][67] cyclin T1,^[68]SRC-1,^[69] retinoblastoma protein,^[70] NRIP1,^[71] estrogen receptor alpha,^[72][73] NEDD8^[74] and ARNTL.[75]

^{The RELA gene}

 

NFKB1 (MIM 164011) or NFKB2 is bound to REL , RELA (this gene), or RELB to form the NF-κB complex. The p50 (NFKB1)/p65 (RELA) heterodimer is the most abundant form of NF-κB. The NF-κB complex is inhibited by IκB (NFKBIA, or NFKBIB), which inactivates NF-κB by trapping it in the cytoplasm. Phosphorylation of serine residues on the I-kappa-B proteins by kinases (IKBKA or IKBKB) marks them for destruction via the ubiquitination pathway, thereby allowing activation of the NF-κB complex. Activated NF-κB complex translocates into the nucleus and binds DNA at kappa-B-binding motifs such as 5-prime GGGRNNYYCC 3-prime or 5-prime HGGARNYYCC 3-prime (where H is A, C, or T; R is an A or G purine; and Y is a C or T pyrimidine).^[2]

Interactions

RELA has been shown to interact with:

• APBA2,^[3]
• AHR,^[4][5]
• ASCC3,^[6]
• BRCA1,^[7]
• BTRC,^[8]
• C-Fos,^[9]
• C-jun,^[9]
• C22orf25,^[10]
• CSNK2A1,^[11]
• CDK9,^[12]
• CEBPB,^[13][14]
• CREBBP,^{[15][16][17][18][19]}
• CSNK2A2,^[11]
• DHX9,^[20]
• EP300,^[19][21]
• ETHE1,^[22]
• FUS,^[23]
• HDAC1,^[16][21][24]
• HDAC2,^[21][25]
• HDAC3,^[26]
• ING4,^[27]
• IκBα,^{[8][21][26][28][29][30][31]}
• MEN1,^[32]
• MTPN,^[33]
• NCF1,^[34]
• NFKB1,^[35][36]
• NFKB2,^[35][37]
• NFKBIB,^[38][39]
• NFKBIE,^[40]
• NR3C1,^[41][42][43]
• NCOR2,^[44][45]
• PARP1,^[46]
• PIAS3,^[15]
• POU2F1,^[47]
• PPP1R13L,^[48][49]
• PRKCZ,^[50]
• REL,^[29][35][51]
• RFC1,^[52]
• RNF25,^[53]
• SP1,^[54][55]
• STAT3,^[56][57]
• TAF4B,^[58]
• TBP,^[59][60]
• TP53,^[57] and
• TRIB3.^{[61]wikipedia}

 ^{Just the rela gene will create a havoc! one important note several of these gene including the PRKC are upstream from DAB2 which is found depressed in Ovarian cancer!(see TGF-beta pathway as proposed by MSKCC)  The link is there!}

"Cytosolic complex---failure of estrogen receptor in triple negative breast cancer may lead to neoplastic transformation through this path! 

The heparan sulfate on the surface of all adherent cells modulates the actions of a large number of extracellular ligands. Members of both cell surface heparan sulfate proteoglycan families, the transmembrane syndecans and the glycosylphosphoinositide-linked glypicans, bind these ligands and enhance formation of their receptor-signaling complexes. These heparan sulfate proteoglycans also immobilize and regulate the turnover of ligands that act at the cell surface. The extracellular domains of these proteoglycans can be shed from the cell surface, generating soluble heparan sulfate proteoglycans that can inhibit interactions at the cell surface.(bernfield et al)

In fact Heparan sulfate allows the progressive motility of Macrophages on cell/endothelial cell by giving and electrical/covalent liaisons (C-terminal) along the way

 

Heparin-binding EGF-like growth factor interacts with mouse blastocysts independently of ErbB1: a possible role for heparan sulfate proteoglycans and ErbB4 in blastocyst implantation

1. B.C. Paria,
2. K. Elenius

 

According to wikipediaWe have previously shown that the transcription factor Sp1 mediates the stimulatory effects of transforming growth factor-beta1 (TGF-beta1) on type IV collagen gene transcription and protein synthesis, and that estradiol reverses these effects by down-regulating Sp1 activity. Protein kinase casein kinase II (CK2) phosphorylates Egr-1 and prevents its binding to Sp1. We hypothesized that TGF-beta1 stimulates CK2 activity, which in turn activates type IV collagen gene transcription via increased availability of free Sp1.(Zdunek et al)

 

 The aryl hydrocarbon receptor encodes a ligand-activated transcription factor involved in the regulation of biological responses to planar aromatic hydrocarbons. This receptor has been shown to regulate xenobiotic-metabolizing enzymes such as cytochrome P450. Its ligands included a variety of aromatic hydrocarbons. The Aryl hydrocarbon receptor (AhR or AHR) is a member of the family of basic helix-loop-helix transcription factors. The physiological ligands of this receptor are unknown (a proposed endogenous ligand is known, it is 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), which can operate in Dendritic cells, two articles:http://www.pnas.org/content/early/2010/11/09/1009201107, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3396465/) , but it binds several exogenous ligands such as natural plant flavonoids, polyphenolics and indoles, as well as synthetic polycyclic aromatic hydrocarbons and dioxin-like compounds. AhR is a cytosolic transcription factor that is normally inactive, bound to several co-chaperones. Upon ligand binding to chemicals such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the chaperones dissociate resulting in AhR translocating into the nucleus and dimerizing with ARNT (AhR nuclear translocator), leading to changes in gene transcription.

Non-ligand bound Ahr is retained in the cytoplasm as an inactive protein complex consisting of a dimer of Hsp90,^[15][16] prostaglandin E synthase 3 (Ptges3, p23)^{[17][18][19][20]} and a single molecule of the immunophilin-like protein hepatitis B virus X-associated protein 2 (XAP2),^[21] which was previously identified as AhR interacting protein (AIP)^[22] and AhR-activated 9 (ARA9).^[23] The dimer of Hsp90, along with p23, has a multifunctional role in the protection of the receptor from proteolysis, constraining the receptor in a conformation receptive to ligand binding and preventing the premature binding of ARNT.^{[5][18][20][24][25][26]} XAP2 interacts with carboxyl-terminal of Hsp90 and binds to the AhR nuclear localization sequence (NLS) preventing the inappropriate trafficking of the receptor into the nucleus.^{[27][28][29] wikipedia"}

"promoter region of AhR responsive genes. The AhR/ARNT heterodimer directly binds the AHRE/DRE/XRE core sequence in an asymmetric manner such that ARNT binds to 5’-GTG-3’ and AhR binding 5’-TC/TGC-3’.^[39][40] Recent research suggests that a second type of element termed AHRE-II, 5’-CATG(N6)C[T/A]TG-3’, is capable of indirectly acting with the AhR/ARNT complex.^[41][42] Regardless of the response element, the end result is a variety of differential changes in gene expression'. The search for other metabolizing genes induced by Ahr ligands, due to the presence of DREs, has led to the identification of an "Ahr gene battery" of Phase I and Phase II metabolizing enzymes consisting of CYP1A1, CYP1A2, CYP1B1, NQO1, ALDH3A1, UGT1A2 and GSTA1.^[58] Presumably, vertebrates have this function to be able to detect a wide range of chemicals, indicated by the wide range of substrates Ahr is able to bind and facilitate their biotransformation and elimination. The AhR may also signal the presence of toxic chemicals in food and cause aversion of such foods.^[59]
AhR activation seems to be also important for immunological responses and inhibiting inflammation.^{[49][60] wikipedia}
" In addition to the protein interactions mentioned above, AhR has also been shown to interact with RELA,^[66][67] cyclin T1,^[68]SRC-1,^[69] retinoblastoma protein,^[70] NRIP1,^[71] estrogen receptor alpha,^[72][73] NEDD8^[74] and ARNTL.^[75]

Direct interaction of c-Myc with Smad2 and Smad3 to inhibit TGF-beta-mediated induction of the CDK inhibitor p15(Ink4B).

Feng XH, Liang YY, Liang M, Zhai W, Lin X

Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA. xialin@bcm.tmc.edu

The c-Myc oncogene has been implicated in the genesis of diverse human tumors. Ectopic expression of the c-Myc gene in cultured epithelial cells causes resistance to the antiproliferative effects of TGF-beta. However, little is known about the precise mechanisms of c-Myc-mediated TGF-beta resistance. In this study, we reveal that c-Myc physically interacts with Smad2 and Smad3, two specific signal transducers involved in TGF-beta signaling. Through its direct interaction with Smads, c-Myc binds to the Sp1-Smad complex on the promoter of the p15(Ink4B) gene, thereby inhibiting the TGF-beta-induced transcriptional activity of Sp1 and Smad/Sp1-dependent transcription of the p15(Ink4B) gene. These results suggest that oncogenic c-Myc promotes cell growth and cancer development partly by inhibiting the growth inhibitory functions of Smads.

Mesh Terms:
Cell Cycle Proteins, Cell Line, Cyclin-Dependent Kinase Inhibitor p15, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinases, DNA-Binding Proteins, Humans, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins c-myc, Receptors, Transforming Growth Factor beta, Signal Transduction, Smad2 Protein, Smad3 Protein, Sp1 Transcription Factor, Trans-Activators, Transforming Growth Factor beta, Tumor Suppressor Proteins

 <sup>======================================================================

THESE ARE THE COMPELLING FACTS IN THE LITERATURE!
NEXT BLOG PUT ALL TOGETHER!</sup>

THE ADAMTS FAMILY!

PLAY WITH THE ADAMTS

ADAMTS1. A disintegrin and metalloproteinase with thrombospondin motifs 1, has anti-angiogenic activity. The expression of this gene may be associated with various inflammatory processes as well as development of cancer cachexia. This gene is likely to be necessary for normal growth, fertility, and organ morphology and function.^[2]ADAMTS1 has been shown to interact with Vascular endothelial growth factor A.<sup>[3]

ADAMTS2. procollagen I N-proteinase (PC I-NP) is an enzyme[ 
Ehlers-Danlos syndrome, dermatosparaxis type is caused by mutations in the ADAMTS2 gene.</sup>

 3.The protein encoded by this gene is the major procollagen II N-propeptidase. A deficiency of this protein may be responsible for dermatosparaxis, a genetic defect of connective tissues. [provided by RefSeq, Jul 2008

4.The enzyme encoded by this gene lacks a C-terminal TS motif. It is responsible for the degradation of aggrecan, a major proteoglycan of cartilage, and brevican, a brain-specific extracellular matrix protein. The cleavage of aggrecan and brevican suggests key roles of this enzyme in arthritic disease and in the central nervous system, potentially, in the progression of glioma.^[2]
5.The enzyme encoded by this gene contains two C-terminal TS motifs and functions as aggrecanase to cleave aggrecan, a major proteoglycan of cartilage.^[3]

Clinical significance

Genetically modified mice in which the catalytic domain of ADAMTS5 was deleted are resistant to cartilage destruction in an experimental model of osteoarthritis.^[4] ADAMTS5 is the major aggrecanase in mouse cartilage in a mouse model of inflammatory arthritis.<sup>[5]

6.CLEARLY POORLY STUDIED, ?PROHORMONE CONVERTASE

7.</sup>ADAMTS-7: a metalloproteinase that directly binds to and degrades cartilage oligomeric matrix protein
Chuan-ju Liu^*


IT IS SAID TO BE INCREASED IN RHEUMATOID ARTHRITIS
SO BLOCK METALLOPROTEASE 7, NO MORE DESTRUCTION OF YOUR KNEES!

8.A number of disorders have been mapped in the vicinity of this gene, most notably lung neoplasms.^[2]

 ADAMTS-8 indicated promoter hypermethylation in one out of 24 brain tumours (a metastasis) and three out of four glioma cell lines suggesting an alternative mechanism of downregulation. These data suggest a role for ADAMTS-8 in brain tumorigenesis, warranting further investigation into its role in regulation of tumour angiogenesis and local invasion.

Expression of ADAMTS-8, a secreted protease with antiangiogenic properties, is downregulated in brain tumours

J R Dunn,<sup>1,*ET AL.

?PROGNOSTIC VALUE IN BRAIN TUMOR OR RESISTANCE TO AVASTIN INDICATOR?

AND YOU CAN PLAY THIS GAME ALL DAY
(TO BE CONTINUED)</sup>

You want to follow where science is going?

"Recently, there was a bit of an internet uproar when some outlets took an interview that Church gave a German newspaper out of context and made it sound as if he were looking to clone Neanderthals. He’s not. But this is the kind of technology that one would use to bring back Neanderthals or, for that matter, mammoths, when their actual DNA is lost to time. Church has said that, in theory, this could be done by changing the genes of a human stem cell (in the case of a Neanderthal) or an elephant (in the case of the mammoth) to match a prehistoric relative. If you want to bring back ice age animals, Cas9 might be the way to do it."   M.Harper...go to article

RECEPTOR FAILURE IS DRIVING TRIPLE NEGATIVE BREAST CANCER.

The official explanation for cancer pathogenesis for the breast by wikipedia  :

Cancer

Estrogen receptors are over-expressed in around 70% of breast cancer cases, referred to as "ER-positive", and can be demonstrated in such tissues using immunohistochemistry. Two hypotheses have been proposed to explain why this causes tumorigenesis, and the available evidence suggests that both mechanisms contribute:

• First, binding of estrogen to the ER stimulates proliferation of mammary cells, with the resulting increase in cell division and DNA replication, leading to mutations.

• Second, estrogen metabolism produces genotoxic waste.

The result of both processes is disruption of cell cycle, apoptosis and DNA repair, and, therefore, tumour formation. ERα is certainly associated with more differentiated tumours, while evidence that ERβ is involved is controversial. Different versions of the ESR1 gene have been identified (with single-nucleotide polymorphisms) and are associated with different risks of developing breast cancer.^[18]
Endocrine therapy for breast cancer involves selective estrogen receptor modulators (SERMS), such as tamoxifen, which behave as ER antagonists in breast tissue, or aromatase inhibitors, such as anastrozole. ER status is used to determine sensitivity of breast cancer lesions to tamoxifen and aromatase inhibitors.^[25] Another SERM, raloxifene, has been used as a preventive chemotherapy for women judged to have a high risk of developing breast cancer.^[26] Another chemotherapeutic anti-estrogen, ICI 182,780 (Faslodex), which acts as a complete antagonist, also promotes degradation of the estrogen receptor.
Estrogen and the ERs have also been implicated in breast cancer, ovarian cancer, colon cancer, prostate cancer, and endometrial cancer. Advanced colon cancer is associated with a loss of ERβ, the predominant ER in colon tissue, and colon cancer is treated with ERβ-specific agonists.^[27]
Phytoestrogens such as quercetin can modulate estrogen receptor’s activities in such a way that it may prevent cancers including breasts, prostate, and colon all by promoting apoptosis.^[28] Quercetin selectively binds to the estrogen receptor beta (ERβ).^[29] This was tested in HeLa cells which were treated with a pure estrogen receptor antagonist which blocked both estradiol and quercetin from inducing the caspase-3 activation.^[28] ERβ is expressed in the human colon and activates a specific signal transduction pathway that controls apoptosis in the colon and works by being activated by estradiol and more recently found to possibly be activated by quercetin.^[28] Quercetin activates the ERβ along with the apoptotic cascade when caspase-3 is present by the phosphorylation of p38 kinase. In colon cancers and tumors ERβ and its pathway have been proven to be significantly decreased thus allowing the tumors to thrive.<sup>[30]

 ------------------------------------------------------------------------------------------------------------------------------------------------
This pathogenesis does not however explain the triple Negative scenario where receptor are supposedly "inexistant" and are not stimulated by Estrogen.  Failure of the receptor leads to secondary stimulation of "unplanned receptor" 
the man pathways are not the same, the stress MAPK , c-JUN is the one over expressed in our proposed model, The failure is a deficiency in the Heparan sulfate component.  In most case the defect is congenital. It take years of  stimulation for normal gene to take a neoplastic shift, that time can be 20-40 years.  That's why these condition are seen in the young. (ie in polycystic kidney diseases it take 30-40 years to start developing kidney failure and a full blown terminal syndrome killing the individual in the 50s and rarely early 60s).</sup>

JUST SO YOU KNOW ....SHORTAGE IS THE NEW VAGUE!

SUBJECT:       Shortage of Xenon Gas (Xe133)

THE Hospital has been informed by our radiopharmaceutical supplier that there is a national shortage of Xenon Gas (Xe133), the gas used for nuclear medicine VQ Scans.  We will be unable to perform the nuclear medicine VQ scans until further Xenon Gas is supplied, hopefully in the next few weeks.  In the meantime, please consult our Radiology Department for studies that can be performed in lieu of the nuclear medicine VQ scan.

Thanks for your attention to this matter.

CANCER CELLS OPERATE IN THE "STRESS MODE"

KNOWING THE FACT THAT IT MAY NOT MEET ITS ENERGY REQUIRED TO UNDERGO ALL ITS NEW FUNCTIONS CALLED FOR BY ITS TRANSFORMATION, CANCER CELLS TURN ON THEIR STRESS "MODE". ON TOP OF PUTTING IN PLACE MECHANISMS TO ESCAPE IMMUNE SURVEILLANCE, TOLERATE GENETIC ABNORMALITIES BY PARALYZING AMONG OTHER THINGS P53, THE CANCER HAPPENS TO FUNCTION IN SOMEWHAT A "HYPOXIC" MOOD.

AND THEN YOU READ THIS!

Hypoxia induces epithelial-mesenchymal transition via activation of SNAI1 by hypoxia-inducible factor -1alpha in hepatocellular carcinoma Full Text
BMC Cancer, 05/18/2013  Clinical Article

Zhang L et al. – In this study, the authors investigate the molecular mechanism by which hypoxia promotes hepatocellular carcinoma (HCC)invasion and metastasis through inducing epithelial–mesenchymal transition (EMT). They demonstrated that hypoxia–stabilized HIF1alpha promoted EMT through increasing SNAI1 transcription in HCC cells. This data provided a potential therapeutic target for HCC treatment."

AND YOU KNOW CANCER WILL BE ON THE MOVE SOON

BECAUSE THIS IS THE WAY TO ENDOTHELIAL TRANSFORMATION AND WITH ENDOTHELIAL TRANSFORMATION COMES MOVEMENT OF CELLS TOWARD ORGAN RIPE FOR SEEDING! YES WITH ENDOTHELIAL TRANSFORMATION, THE E-CADHERIN IS SUPPRESSED, RECEPTORS OF THE CELLS CHANGE IN NATURE AND THE CELL RELEASE SOME OF THE ADHESION PROTEINS, AND IT IS ON THE MOVE!  IN THIS MODE, IT WILL BE ALSO LESS DEPENDENT TEMPORARILY ON ITS GROWTH FACTORS!

AND WHAT GENES COMES WITH ALL THIS ENDOTHELIAL TRANSFORMATION?

RBSP3, HYA 22, APO22, APRG1, ITGA2, VILL (SMAD AND CDK9 ARE IN THE WING)

YOU JUST KNOW SOMETHING IS BIG CELL WISE WHEN RNA POLYMERASE IN INVOLVED BECAUSE DNA POLYMERASE FOLLOWS WITH THE REST OF THE KITTEN CABOODLE THAT LEADS TO NEW PROTEIN FORMATION THAT WILL IMPACT CELLULAR METABOLISM ! MEK IS SOMEWHERE ACTING TOO...

RENEWED INTEREST IN CDK-9

Cyclin-dependent kinase 9

From Wikipedia, the free encyclopedia

Jump to: navigation, search

Cyclin-dependent kinase 9
Rendering based on PDB 1PF6.
Available structures PDB Ortholog search: PDBe, RCSB [show]List of PDB id codes
Identifiers
Symbols	CDK9; C-2k; CDC2L4; CTK1; PITALRE; TAK
External IDs	OMIM: 603251 MGI: 1328368 HomoloGene: 55566 ChEMBL: 3116 GeneCards: CDK9 Gene
EC number	2.7.11.22, 2.7.11.23
[show]Gene Ontology
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1025	107951
Ensembl	ENSG00000136807	ENSMUSG00000009555
UniProt	P50750	Q99J95
RefSeq (mRNA)	NM_001261	NM_130860
RefSeq (protein)	NP_001252	NP_570930
Location (UCSC)	Chr 9: 130.55 – 130.55 Mb	Chr 2: 32.71 – 32.71 Mb
PubMed search	[1]	[2]
This box: view talk edit

Cyclin-dependent kinase 9 or CDK9 is a cyclin-dependent kinase associated with P-TEFb. The protein encoded by this gene is a member of the cyclin-dependent protein kinase (CDK) family. CDK family members are highly similar to the gene products of S. cerevisiae cdc28, and S. pombe cdc2, and known as important cell cycle regulators. This kinase was found to be a component of the multiprotein complex TAK/P-TEFb, which is an elongation factor for RNA polymerase II-directed transcription and functions by phosphorylating the C-terminal domain of the largest subunit of RNA polymerase II. This protein forms a complex with and is regulated by its regulatory subunit cyclin T or cyclin K. HIV-1 Tat protein was found to interact with this protein and cyclin T, which suggested a possible involvement of this protein in AIDS.^[1] CDK9 is also known to associate with other proteins such as TRAF2, and be involved in differentiation of skeletal muscle.^[2]

Interactions

CDK9 has been shown to interact with Cyclin K,^[3] Cyclin T2,^[4] RELA,^[5] Cyclin T1,^{[3][4][6][7][8][9][10][11][12]} Retinoblastoma protein,^[13] Androgen receptor,^[14] SKP1A,^[10] MYBL2,^[11] CDC34^[10] and SUPT5H.<sup>[12]

(TO BE CONTINUED!)</sup>

JUMP ON THE BANDWAGON QUICK

The success of T-DM1, an Herceptin combination with Entansine, is a significant progress that marks elective delivery of Chemotherapy to specific cells carrying the receptor for Trastuzumab.  It addresses one of the most critical step in the cancer fight.  That is how to selectively hit the cancer cell, sparing normal cells best you can.   This advance would not have been  possible without the knowledge and detection of Herceptin receptor in the first place.  This is an example of how knowledge from before is being used to build on for future knowledge!
Possessing the technology to use known receptor this way in order to deliver a drug to the cancer cell electively is now the new rush. And drug development companies around the world are in fierce competition to try to better command this technology!  PSA (prostate specific antigen), MUC2 receptors have been used to deliver drugs specifically to prostate and lung cancers.  (OOKAWA et al.  "breast cancer and A427 lung cancer cells, MUC2 expression was increased along with the endogenous p53 level by actinomycin D, UVC, and x-ray, but not in RERF-LC-MS lung cancer cells carrying a mutated p53. These results suggest that p53 directly activates the MUC2 gene in many cell types.")-lung cancer cells like the bowel, have MUC2, I am not just making up this stuff, and here you see the link with P53, take a quick note!

Coming back to our subject at hand, companies around the world are jumping on the band wagon to dominate and command this technique on selective hit to cancer.  And I am sure you understand why?  while we are now giving now powerful drug (drug that are 10x the current chemotherapies in strength)  next we will be giving selective blow to driver genes in cancer and if remember the number of genes, the potential for this technology becomes  quickly endless!

Cancer cells have a set of Receptors that is different from their normal counterpart.  Knowing this difference is critical in the design of this therapeutic approach. We are still waiting from CPRIT  results of some of the projects working on this.  But it will be a major development if  such a panoply of receptors are proposed through these companies to develop future projects!  It is now clear that knowing more receptors is critical for new drug development!

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CONFERENCES

CME

SUPPLEMENTS

 

REVIEW ARTICLE  Advances in the Systemic Treatment of Metastatic Melanoma By Melinda Yushak, MD, MPH1, Harriet M. Kluger, MD1, Mario Sznol, MD1 | May 15, 2013 1Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut ABSTRACT: Prior to 2011, the only commercially available agents commonly used to treat metastatic melanoma—including dacarbazine(Drug information on dacarbazine), temozolomide(Drug information on temozolomide) (Temodar), fotemustine, carboplatin(Drug information on carboplatin), paclitaxel(Drug information on paclitaxel), and interleukin-2—demonstrated limited efficacy, and no study involving these agents had shown an improvement in overall survival. The standard of care for the treatment of metastatic melanoma was radically changed by the subsequent approval of two agents, ipilimumab (Yervoy) and vemurafenib (Zelboraf), both of which improved survival in randomized phase III trials. Within the relatively short time that ipilimumab and vemurafenib have been commercially available, phase II data for the investigational agents nivolumab and MK-3475, for the combination of dabrafenib and trametinib, and for adoptive cell therapy strongly suggest even further improvements in treatment outcomes. Within this rich context of effective agents, the challenge for clinicians and investigators will be to develop predictive biomarkers of response, the optimal sequence of therapy for individual patients, and effective combinations. An additional challenge will be to find the appropriate venue and populations to test promising new agents arising from substantial advances in our understanding of molecular alterations in melanoma cells, of mechanisms of resistance to current agents, and of tumor-host immune interactions. ==========================     GO TO ARTICLE FOR FURTHER DETAILS!   http://www.cancernetwork.com/melanoma-skin-cancer/content/article/10165/2141794?GUID=EA9DCCFA-913B-4D15-898B-076D1A88BBD6&rememberme=1&ts=16052013

WE KEEP AN EYE ON BREAST CANCER INFORMATION!

*Fulvestran at 500 mg is probably the strongest hormone intervention in post Menopausal patients.
*Switching from Letrozole to tamoxifen after 2 years has NO  loss in survival benefit,  so if Osteoporosis is worsened on Letrozole, switch easy! 
*Docetaxel +Herceptin+Pertuzumab is best first line treatment of Her-2 positive  metastatic breast cancer .
*Don't give T-DM1 with Herceptin because they compete for same receptor and mitigate the power of T-DM1
*Tamoxifen has a "carry over" effect.  Even when you stop it, it keeps on going (like the Battery!)

"Water Trapped For 1.5 Billion Years Could Hold Ancient Life"

(by Adam Cole)

BUT AT THE CRBCM ALL I COULD WONDER  IS WHAT KIND OF GENOME WE WILL UNCOVER!  THIS IS EXCITING. LET'S MAKE SURE THE HUMAN GENOME PROGRAM PARTICIPATES  IN THIS NEW VENTURE!  ARE THERE DIFFERENCES WE CAN LEARN FROM?
GO TO THE ORIGINAL ARTICLE BY ADAM COLE, AND CANADA WAS THE PLACE OF DISCOVERY !

BRACE YOURSELF:IMMUNOTHERAPY IS COMING TO OVARIAN AND SOON TO PANCREATIC CANCERS!

YES, THE MAGIC BULLETS DREAMED REPORTEDLY BY PAUL EHRLICH ARE COMING TO CANCERS!
DMUC5754A HAS SHOWN SOME ACTIVITY IN OVARIAN CANCERS.  LIKE T-DM1, IT IS A CONJUGATE OF A DRUG (ONLY KNOWN AS MMAE) AND AN ANTIBODY TO MUC-16 PROTEIN WHICH IS EXPRESSED IN OVARIAN CANCER, SEE OUR DISCUSSION ON VARIOUS MUC !

REMEMBER: A HIGHER DOSE OF FASLODEX (500 MG vs 250MG) SHOWED A 19% REDUCTION IN RELATIVE RISK OF DEATH AND A MEDIAN SURVIVAL OF 26.4 MONTHS VS 22.3 MONTHS. SO CHOOSE TO GIVE 500 MG EVEN IN PATIENTS WHO HAD BEEN STARTED ON 250 MG BY SOMEBODY ELSE, KEEPING THEM ON THE DOSE MAY NOT BE THE BEST CHOICE FOR OUR PATIENTS! (ONLY MAYBE IF THE PATIENT HAS BEEN ON 250 MG FOR MORE THAN 50 MONTHS WHERE THE DIFFERENCE OF SURVIVAL SEEMS TO NO LONGER BE STATISTICALLY SIGNIFICANT!

DON'T BE FOOLED, BREAST CANCER IN YOUNGER WOMEN IS ON THE RISE AND THEREFORE YOUR CHANCE OF BEING CONFRONTED BY A YOUNG WOMAN WITH BREAST CANCER IS SOMEWHAT HIGHER EVERYDAY!

ADDING BORTEZOMIB TO STANDARD INDUCTION OF AML IS AN EXAMPLE OF TARGETING THERAPY IN-ROD INTO LEUKEMIA AND EARLY REPORTS SUGGEST IT IS SOMETHING TO FOLLOW. RESEARCHERS ARE LOOKING AT THE EXPRESSION OF CD 74 TO SEE IF IT WILL HELP PREDICT THE OUTCOME. WE WILL FOLLOW THIS FOR YOU!

MORE VARIOUS NEWS

*According to a report by Alice Goodman, a higher expression of Her-2 was linked to best results with T-DM1.
This was concluded from the EMILIA trial.

*Full node dissection after positive sentinel is raising controversy among Surgeons involved in the discussion for its value!
Proponents maintained that:
1. Full node dissection  has staging value
2. Full node dissection decreases regional recurrence risk

Opponents maintain:
- It is an unnecessary and costly operation because 80% of pt with positive nodes have distant disease anyway
- Lymphedema risk worsens particularly with groin dissection
- Increased infection risk and nerve damage potential
that good result is linked to patient selection
- FULL DISSECTION DOES NOT INCREASE SURVIVAL.

HOWEVER, GAMBLING WITH MELANOMA IS A LITTLE MORE RISKY THAN IN BREAST CANCER. THE DIFFERENCE OF PROGNOSIS IN METASTATIC DISEASE TELLS IT ALL!  THE LACK OF DIFFERENCE IN SURVIVAL IS HOWEVER A SIGNIFICANT HURDLE TO CONCUR!

EMBRACE THE CHANGES OR DIE

With the progress in genetics, the field of Oncology is bound to change.  The volume of work done in the field of genetics as it relates to oncology, has moved this field from what it was, a research area, to center stage daily Oncology practice.  Knowledge of CHOP and combination Etoposide -Cisplatin or even Taxol-Carboplatin indications, is shrinking in importance in the Ipilimumab and Crizotinib world.  The thing is as we getting closer to actually cure cancer we have understood that knowing more about natural chemical pathways in the cell, and treating cancer based on this knowledge has yielded better results in response rates and disease free progression and sometimes in overall survival.  This evidence has convinced most Oncologists that it is time to move to the Target therapy movement and brace our selves for the new "TARGETOLOGY" IN MEDICAL ONCOLOGY.
TARGETOLOGY IS NOT JUST THE STUDY OF CELLULAR TARGETS, it is the full command of treatments that address the law of Nature.
- Genes controlling DNA, DNA repair, DNA stability, and mechanisms therewith to maintain the integrity of the Nuclear Material and its Epigenetic environment.
-  Genes involved in key the Cellular pathways and corollary pathways
- Genes of proliferation
- Genes of cellular metabolism amplification and regulator genes
- Genes of differentiation (Mesangial and endodermal transformation vs epithelialization)
- Genes of Cellular Adaptation
- Genes of electrical conduction and hidden pathways (Wnt, Notch)
- Genes controlling cellular adaptation
- Genes driving Metastasis, transport and membrane vacuole formation
- Genes  of Receptors and cellular Adhesion
We should stress that the mechanisms used by the cell to impose the direction of Homeostasis based on flight or stay needs, response to environment stimuli, and sense of purpose imposed by the notch and cell differentiation.  The notion of Core Binding Factor should be extended to all protein complexes imposing cellular Metabolism direction as it is evident that that's how the cell operates!
The notion that some Cancers use specific drivers that can be somewhat is easily identified (CML) vs cancers that are using regulator enzymes (certain Leukemias) or epigenic events, should be brought forth.
Some proliferative disorders find their driver effect in shifts in gene Methylation or splicing patterns rather than actually in changing or mutating genes.  But clearly, most cancers come from a failure of receptors with subsequent increase of growth factors which end up imposing growth and Mutations in unwanted areas!  Among the unrecognized mechanisms is deficiency of location of important effector proteins.  In other words, failure in transport. Traffic has to go on from Membranes to Nucleus, transport failure for one reason or another, failure of vacuolization that allows exocytosis, function of Golgi apparatus and  lysozome. Do not forget the Ribosome and Mitochondria!  Some of the organelles are so important that they have their own genome!
The point is that it is time to now be reacquainted with cell biology to be an efficient Oncologist because that is where the answer is!  Avoiding this fact will not cut it!  It is the way to the future! Manipulating chemical destruction by using standard chemotherapy has failed to give more cures!  We have met drug resistance and the power of cell adaptatio. It is past time to rethink our strategies and Targetology is here now and to stay!