Lung Cancer Newsletter February

Lung Cancer Newsletter February 2009

keywords, lung cancer newsletter, new treatments, non-small cell lung cancer treatment, newsletter, book, small cell lung cancer, experimental treatments, lung cancer newsletter.

1. Approaches to Treatment

A. Targeted Treatment

Do cancers, even of the same organ, have subtle differences that can help determine prognosis and and impact treatment. That is one theme of treatment in the 21^st century. The approach was prompted by discovery that Tarceva treatment had a modest 10% response rate, but 60% for EGFR positive patients. Can we test patients for the offending growth factor, and craft individualized cures. The discovery has not yet provided a cure, as EGFR positives patients patients encountered resistance, as the cancers unveiled new abnormal cell system signaling to thwart new drugs.

While the testing of EGFR has a sound basis, can we go beyond EGFR to test for other growth factors and mutations, and create treatment based upon individualized assessments, and refine that treatment through followup testing.

2. Tarceva

A. Overview

The overall response rate to Tarceva is modest, about 10%. However, patients with a mutation in the epidermal growth factor receptor (EGFR) have an impressive 60% response rate. These are principally non-smokers with adenocarcinoma or BAC, though some light former smokers and a few others are found with the mutation.

Many of these patients develop a secondary MET or T790M mutation that is Tarceva resistant. New drugs, particularly pan-inhibitors, are being tested to address this.

Evolving research is showing that certain mutations areas have distinctive characteristics. A database is being compiled to categorize the various types of EGFR mutations and their responses. egfr-mutations.org Astute patients may want to determine the type and location of their mutation through testing, and tract its behavior through followup testing.

B. KRAS Mutation

KRAS mutations has been a negative indication of response. Most non-smokers who are EGFR positive do not have the KRAS mutation, while many smokers and EGFR negative patients have the KRAS mutation. Garcia, KRAS mutational testing in the selection of patients for EGFR-targeted therapies, Semin Diagn Pathol. 2008 Nov;25(4):288-94. Miller found, “No patient (zero of 18; 95% CI, 0% to 19%) whose tumor harbored a KRAS mutation responded to erlotinib (Tarceva).” Miller, Molecular characteristics of bronchioloalveolar carcinoma and adenocarcinoma, bronchioloalveolar carcinoma subtype, predict response to erlotinib, J Clin Oncol. 2008 Mar 20;26(9):1472-8

C. T790M Mutation

1. Overview

A majority of EGFR positive patients enjoy an impressive initial response. Subsequently however, many develop a secondary mutation at T790M which is estimated to be responsible for about 50% of Tarceva resistance. New drugs are being developed to combat the T790M mutation, primarily pan-inhibitors,

Two resistance mechanisms have so far been identified: a secondary mutation in the EGFR gene, T790M, and amplification of the MET proto-oncogene. This review willcentre on T790M, which is thought to cause steric hindrance and impair the binding of gefitinib/erlotinib. A novel class of irreversible TKIs currently under development may retain activity against some common resistance mechanisms, including T790M. The next challenge is to identify accurately the subgroup of patients with NSCLC whose tumours harbour EGFR T790M. To this end, post-treatment tumour specimens will be needed to establish molecular profiles for each patient. In addition, novel, highly sensitive technology will be required to detect these mutations. This is because allelic dilution, whereby the EGFR gene is amplified but only a few copies of the T790M allele are needed to confer resistance. Janne, Challenges of detecting EGFR T790M in gefitinib/erlotinib-resistant tumours, Lung Cancer. 2008 Jun;60 Suppl 2:S3-9

2. Chemical makeup and method of resistance by T790M

A secondary point mutation that substitutes methionine for threonine at amino acid position 790 (T790M) is a molecular mechanism that produces a drug-resistant variant of the targeted kinase. The T790M mutation is present in about half of the lung cancer patients with acquired resistance, and reported to act by increasing the affinity of the receptor to adenosine triphosphate, relative to its affinity to TKIs. Nevertheless, several lines of evidence indicate that the T790M mutation confers growth advantage to cancer cells, and it was shown that mice expressing tetracycline-inducible EGFR transgenes harboring the T790M mutation develop lung tumors. Thus, T790M mutation seems to play a double role in the survival of lung cancer cells. Suda, EGFR T790M mutation: a double role in lung cancer cell survival, J Thorac Oncol. 2009 Jan;4(1):1-4

D. HKI 272

Some initial studies suggested a drug called HKI 272 would be successful in addressing various forms of resistance. Janne found “HKI-272 can overcome T790M resistance only at suprapharmacologic concentrations.” Janne, Challenges of detecting EGFR T790M in gefitinib/erlotinib-resistant tumours, Lung Cancer. 2008 Jun;60 Suppl 2:S3-9. Additioanlly “Our findings suggest that HKI-272 treatment at maximally tolerated dosing may lead to the emergence of T790M-mediated resistance,: Id.

E. MET Oncogene

1. Function

“MET receptor tyrosine kinase and its ligand hepatocyte growth factor (HGF) regulate a variety of cellular functions, many of which can be dysregulated in human cancers. Activated MET signaling can lead to cell motility and scattering, angiogenesis, proliferation, branching morphogenesis, invasion, and eventual metastasis.” Ma, Expression and mutational analysis of MET in human solid cancers. Genes Chromosomes Cancer. 2008 Dec;47(12):1025-37. “The Met oncogene encodes the tyrosine kinase receptor for hepatocyte growth factor (HGF). Uncontrolled activation of Met is oncogenic and has been implicated in the growth, invasion and metastasis in a variety of tumors. Several distinct mechanisms including amplification, translocation or mutation of Met may underlie uncontrolled Met activation.

2. Prognosis for Non-small cell lung cancer

“Among 213 NSCLC patients, increased Met copy number was identified in 12 patients (5.6%) and associated with a worse prognosis.” Okuda, Met gene copy number predicts the prognosis for completely resected non-small cell lung cancer, Cancer Sci. 2008 Nov;99(11):2280-5

F. Celebrex and Tarceva/Iressa combinations

“In this study, we characterize the role of celecoxib in the cytotoxicity, ERK1/2 activation and Rad51 expression affected by gefitinib in NSCLC cells. We show that celecoxib can enhance the cytotoxicity induced by gefitinib in NSCLC cells.” Ko, The role of celecoxib in Rad51 expression and cell survival affected by gefitinib in human non-small cell lung cancer cells. Lung Cancer. 2009 Jan 19

3. Small Cell Lung Cancer

“A study examined factors associated with survival in small cel lung cancer. “Results showed that performance status (PS) 0-1, limited disease, normal serum carcinoembryonic antigen (CEA), and vascular endothelial growth factor (VEGF) level were associated with improved response rate.” Li, Survival and prognostic factors in small cell lung cancer, Med Oncol. 2009 Feb 12. [Epub ahead of print]

4. Non-small Cell Lung Cancer

A. Prognosis in Operable Patients

Univariate analysis showed that high expression of vascular endothelial growth factor A (VEGF-A) (p = 0.004), VEGF receptor-1 (VEGFR-1, p = 0.028), VEGFR-2 (p = 0.021), VEGFR-3 (p = 0.001) and platelet derived growth factor (PDGF) in tumors correlated significantly with a poor survival. Inversely, high basic fibroblast growth factor (bFGF) expression in stroma was associated with significantly improved

4. Vascular Angiogenic Growth Factor

1. Overview

An increasing number of tumour-released angiogenic cytokines which affect vessel formation, tumour growth, invasion, and metastasis have been identified. Vascular endothelial growth factors (VEGFs) and basic fibroblast growth factor (bFGF) are among the most important angiogenic factors. Angiogenesis in non-small cell lung cancer: the prognostic impact of neoangiogenesis and the cytokines VEGF and bFGF in tumours and blood, Lung Cancer. 2006 Feb;51(2):143-58. Epub 2005 Dec 19

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