NOMENCLATURE OF GENES IN SMALL CELL LUNG CANCER

Before we start this discussion, a few comments !

1. It is generally accepted that small cell cancer is found in those patients with higher smoking exposure and, indeed, genetic alterations in small cell cancers are deeper (more nuclear) than those in non small cell cancer.  Mutation in Kras and p16 are not a characteristic of small cell lung cancers, whereas nuclear phenomena abound.  p53 mutation which is driven by DNA alteration is found altered in 90% of small cell lung cancer.

Rb gene mutations which affect resumption of DNA duplication is also altered in 90% of small cell lung cancer (SCLC).

c-MYC amplification, which is located down stream cytoplasmic pathways, at the Histone level, is more observed in SCLC.

By going nuclear, SCLC will not respond effectively to superficial (membrane/ cytoplasmic ) interventions such as EGFR blockade. However, there is a secondary angiogenic amplification usually marked by amplification at FGF2 (target and biomarker) which open the door to anti-angiogenic agents in small cell cancer.  Here researcher have to select between an anti-MEK or an anti-FGF2 or both, if cost is not an issue.  Remember that an anti-MEK will also affect secondary amplification of HiF which exacerbates angiogenesis  (and metastasis indirectly) in this disease! Remember: Digoxin inhibit HIF, and HIF amplify angiogenesis through activation of PDGF-B.

2. p16 effect which is occurring in cytoplasmic pathway will not be a major driving target in SCLC, however there is evidence that secondary cytoplasmic phenomena do occur.

see the work of Pederson et al.

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Transcriptional Gene Expression Profiling of Small Cell Lung Cancer Cells 1

1. Nina Pedersen2,
2. Shila Mortensen2,
3. Susanne B. Sørensen,
4. Mikkel W. Pedersen,
5. Klaus Rieneck,
6. Lone F. Bovin, and
7. Hans Skovgaard Poulsen3

"In the CPH 54 cluster there is also high expression of extracellular matrix proteins, such as a large variety of collagens, fibronectin, and laminin, which are not expressed to the same level by the rest of the SCLC cell lines. This indicates that the cell lines may be of fibroblastoid origin rather than SCLC, although the xenografted tumors from the CPH 54A cell line preserved the pathologically determined features of SCLC (4) . In addition, these are the only cell lines that do not have mutated p53 5 or loss or mutated pRB, two of the characteristics of SCLC (19, 20, 21, 22) . "
"
However, this is the case for another tumor suppressor, CDKN2A (p16INK4), which is a negative regulator of cell proliferation by stabilizing the tumor suppressor pRB. Deletions, reduced expression, or mutations of p16INK4 are observed frequently in a variety of tumors. However, the microarray analyses showed high expression by most SCLC lines and tumors, which is consistent with previous observations of high expression in SCLC tumors (60 , 61) and cell lines (62) . p16INK4 leads to cell cycle arrest in the presence of functional pRB. pRB has been found to be absent or mutated in the majority of SCLC tumors and cell lines (20 , 22 , 63 , 64) . In fact, absence of p16INK4 has been found to be restricted to lung cancer cell lines that retain wild-type pRB (65) . There are two major forms of CDKN2A, p16INK4 and p14ARF, derived by alternative splicing. p14ARF is likewise regarded a tumor suppressor by stabilizing p53, but also has p53-independent cell cycle regulatory functions (66) . The probe sequences on the microarray will recognize both forms. RT-PCR using a p14ARF specific primer set showed expression levels similar to the array analysis (Fig. 4B) ⇓ demonstrating the presence of this mRNA. p14ARF transcription is stimulated by E2F transcriptions factors (67) , and the analysis shows high expression of E2F1 and E2F3 in all of the SCLC cell lines, as has been found previously for most SCLC tumors by immunohistochemistry (68)  "

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SO E2F1 IS A STRONG TARGET.  THIS COMES UP REPEATEDLY IN OUR BLOG! CHECK IT OUT!  IF YOU FIND IT YOU WILL KNOW WHY.

3.By going nuclear, small cell cancer is closer to Leukemia in their pathogenesis, and DNA alteration is a prominent treatment intervention explaining the superiority of Cisplatin Etoposide in this disease.  (watch for DNA repair potential and the Bcl-2 which are ready to fight back!)

4. Hypermethylation is one of the major means used by the cancer cells to suppress some of the genes that could distract the involved cell from a neoplastic differentiation.  It open the door to an added therapy to the Cisplatin and Etoposide back bone.

5. c-MYC and FGF2  amplification can be driven by PTTG1 (securin), a novel target in SCLC.

6. The growth factors in this disease are
-Bombesin/Gastrin releasing Peptide
-Chromogranin B
-Nicotinic Acethylcholine
-securin

QUESTION FOR YOU: DO YOU THINK AMPLIFICATION OF RET PREDICTS HYPERCALCEMIA?  WE ARE STILL WORKING HARD AT CRBCM !

(GENES IN LUNG CANCERS WILL FOLLOW)