NEW GENES ARE BEING INCLUDED IN THE CLINICAL THERAPY OF LUNG CANCERS!

ASIDE FROM THOSE INCORPORATED IN THE GUIDELINES OF ONCOLOGY PRACTICE
1.EGFR
2.ALK

Now we are hearing about the following
1.ROS-1
2.MEK-1
3.RET
4.BRAF
5.HER-2
6.PI3KCA
7.KRAS
8.PD-1,2
9.ERCC1
10.BRCA-1 mRNA
11 P53

What about the therapeutic roles of :
GSTM-1 and GSTT1,FAK, Wnt, Notch, p16,
HIF and VGEF and the CYP1A1,P ?

Real clinical questions

1. Identifying best chemotherapy drugs in patients with Mutation in the NOTCH pathway?
Taxotere?
association with Her-2 overexpression and use of Herceptin
NF-kB blocker
or AKT blocker.
Histone de-acetylator

2. Understanding the patterns of Metastasis between epithelial (squamous) (more local recurrence)  Vs AdenoCA (more distant recurrence in Esophageal cancer? Genes at play.
Does mesenchymalization dictate or drive long distance metastasis?

3. Mitomycin in NFKB amplification/Mutations

Critical importance of the Notch1

TSG1, HGS, and STAM2 appear critical in the importance of the NOTCH1.

We have stressed the importance of the NOTCH in cancer and wanted to provide some of the proof for the supportive evidence found in the literature.  The Notch through its interaction with MAML1, easily affects EP300 leading to activation of TSG, a critical gene in the action of P53.  Indeed P53 acts by activating TSG which leads to an increasing inhibitory activity of p21 on CDKs, blocking as a result cell division and therefore proliferation.
Inhibition at the NOTCH will therefore remove breaks to cell division and will mark a significant tendency to cancer incurability!
And I wish things stop there, but they don't:
The Activation of TSG will disturb the resting HSG which bothers the Merlin and blocks NF2 leading to the loss of growth control by contact of surrounding cells, the cell losing control of its growth...Hyperplasia can easily ensue!
The HSG now excited, engages the STAM2 and 3 things:

1. Interaction with JAK1 leading to metastasis

" Expression of JAK1 in cancer cells enables individual cells to contract, potentially allowing them to escape their tumor and metastasize to other parts of the body (wikipedia)"
the involvement of JAK-1 multiply the worsening of the situation because it will excite: PTPN11

" PTPN11 is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation." 
and with the ELP gene, the process will affect the SMAD3 leading to loss of control of proliferation and normal ubiquitylation of inhibitory proteins.

2.S TAM2 will engage Cytokin Receptors  (Cullins)

3. STAM2 will engage the tract to E3.

But the engagement of the Notch does still not stop there...

the GSK3B comes into play! and ....

The Crux of Tumorgenesis

The secret of cancer proliferation and persistence lays in phenomena at the membrane, where the NOTCH, Wnt and Hedgehog are located.  These functions of the membrane start and drive the cancer with help from the ABCG2, MRp1, Pgp gene;  it gives it resistance to powerful medications (Adriamycin, CPT11), with SuFu/PEX it reaches a gene capable of inducing malformation, with FOXM1, proliferation is guaranteed, through GLI1, Cyclin D2 is reached. Differentiation is reached though the MEK and failure of control is assured by dysregulation at the FAK.  The Cancer's mind set is driven by the FOXM1 for sure.  Other genes involve the NANOG, the PTCH1, The SOX and the OCT, CDH1, Shh,Twist, Plakoglobulin...

Profiling through at the CRBCM!

At the CRBCM something is coming through:

1. Deterioration at membrane receptor by lack of stimulation or "false or abnormal stimulation" could not only alter the nature of the "glycan" covering the protein portion of the receptor, but also induce stress like molecules.(HSP)
2. As a result of receptor failure new cytokines and TGFs are secreted which unfortunately fail at the initial receptor, but induce other receptors, amplifying standard pathways like RAS or PIK
3. Certains TGFs have an intrinsic power to maintain life of cells no matter what and induce metastasis.
4. Certain genes have an auto-phosphorylation or self-limiting mechanism that can easily go wrong  (RAS, FAK) driving to neoplastic process
5. FAK plays a larger role in aggressive prostate cancer than it has been recognized!
6. FAK has a closer relation to Androgen than recognized
7. NOTCH has closer relation with MEK and "stem cell potential" than recognized.
8. FAK disturbance prominence in cancer explains its sensitivity to Taxanes!  That is on top of Microtubule disturbances induced by the drug!
9. Metalloproteases are the ultimate Biomarkers of membrane events !
10.  Epigenetic methylation and its patterns are one of the largest mystery still to be elucidated!