Lung Cancer Program: Vision for the Next Decade

 

 
Some of the most significant research at LRRI is in the lung cancer program.  LRRI scientists  focus on using the basic laboratory setting to identify critical determinants that regulate genes and pathways whose function may prove valuable as biomarkers for early detection, for monitoring disease recurrence, and as targets for therapy.
 

 

In collaboration with clients and special protocols, this knowledge is then translated into populations (either the smoker at risk or the lung cancer patient) to assess initial performance of the biomarker or efficacy of modulating the pathway therapeutically. Two examples of this approach are as follows: silencing of the p16 tumor suppressor gene was shown by LRRI scientists to be a common event in non-small cell lung cancer, and to occur in precursor lesions. This finding was then translated to the population setting to ask whether detection of methylation of p16 in sputum from persons at high-risk for lung cancer could predict incident cancer. In another example, laboratory studies have determined that >50 genes may be silenced in a lung tumor through methylation, and the ability to reverse this epigenetic process has led to a Phase I/II clinical trial of demethylation therapy in lung cancer patients.

Building on these and other exciting advances over the past 5–10 years, the goals of the Lung Cancer Program are to:

  • Identify mechanisms for gene targeting and silencing by tobacco carcinogens and the role of DNA damage and repair
  • Validate gene promoter methylation in sputum as a biomarker for incident lung cancer detection, prognosis, and for monitoring intervention therapy
  • Identify ethnic differences underlying susceptibility for lung cancer
  • Develop novel therapies for primary and secondary lung cancer prevention

Developing aerosol delivery of drugs for cancer treatment and prevention

An in vitro model has been developed that allows LRRI to systematically assess the role of genes in the nucleotide excision and double-strand break DNA repair pathways by using siRNA to reduce expression of these genes in immortalized bronchial epithelial cells.

Functional assays (chromatid break and micronuclei) have been developed to assess the effect that reduced gene activity in the setting of carcinogen exposure has on DNA repair capacity. Following the identification of genes that are rate limiting for repair, subchronic exposure to carcinogens is initiated and time to transformation and gene promoter methylation is assessed.

Recent studies have already demonstrated in repair competent cells the ability of carcinogen exposure to induce silencing of specific tumor suppressor genes, most notably the cadherins, modulate protein levels of the major cytosine DNA methyltransferase, and induce transformation.

A major goal for the lung cancer program has been to develop a sputum-based diagnostic test for detection of early incident lung cancer. Using both a candidate gene and gene discovery approaches, scientists are nearing the completion of screening approximately 60 genes as biomarkers for early detection of lung cancer. This work has been conducted through a nested, case-control study within the Colorado cohort of smokers with chronic obstructive pulmonary disease.

The penultimate marker panel will be validated through a two-step process over the next 3–4 years. Marker performance will be assessed in sputum from approximately 800 early stage I lung cancer patients enrolled through the New Mexico Lung Cancer cohort, MAYO, Johns Hopkins, and Colorado and compared to sputum obtained from persons at risk for lung cancer being enrolled in Albuquerque (Lovelace Smokers Cohort) and Colorado. The gene panel that shows the highest sensitivity and specificity will then be validated through a nested case-control study within the ACRIN cohort (7,500 participants within the National Lung Cancer Screening trial who are providing longitudinal sputum specimens). These validation studies will allow assessment of sensitivity, specificity, and overall positive and negative predictive value of the gene panel in the ACRIN cohort for lung cancer detection.

The identification of genetic determinants for gene promoter hypermethylation and genotypes associated with lung cancer could help to further refine a risk model for lung cancer. Highlights of these activities include demonstrating a strong association between reduced DNA repair capacity and methylation index (three or more genes methylated) in sputum and conduct of an Illumina assay for 62 genes in cases and controls defined either by methylation index or cancer status.

The association of specific genotypes of genes within the double-strand break repair pathway to DNA repair capacity and methylation index has been identified. Analysis of other genes on the OPA involved in methylation, apoptosis, carcinogen metabolism, and single-strand break repair are underway. These pilot studies are identifying genotypes that will be further characterized in larger case-control studies. In addition, whole genome screening studies using established populations are being designed for future studies.

Although Hispanic lung cancer incidence rates are decreasing nationwide, rates in New Mexico Hispanics are increasing. Recent studies suggest ethnic differences in lung cancer risk independent of cigarette smoking may also play a role in overall susceptibility to this disease. A goal for the lung cancer program is to create a statewide registry for Hispanic lung cancer patients and to conduct candidate gene haplotype analysis and whole genome screening using a case-control design.

Key to reducing mortality from lung cancer will require early detection, more effective therapeutics approaches, and the development of primary and secondary prevention. Our strategy over the next decade will be to develop cocktails of agents commonly used to treat non-neoplastic diseases that also affect growth of cancer cells. Animal models will be used to evaluate the efficacy of these agents to prevent progression of preneoplastic lung disease. These agents will then be tested in Phase I/II studies first in resected lung cancer patients and then in persons at high risk for cancer. Outcome will be assessed by prevalence for recurrence and/or reduction in field cancerization as detected by a decrease in methylation index in sputum. Highlights of these activities include the ability of treatment with a PPAR g agonist, inhibitor of histone deacetylation, and a demethylating agent to dramatically block progression and reduce the size of adenomas in the A/J mouse lung cancer model. Combinatory approaches to treatment of lung cancer both in the clinic and in animal models are evaluating cocktails of agents that cause 5-methylcytosine demethylation, inhibit class I/II/III histone deacetylation, and block a key histonemethyltransferases. Finally, in vitro studies suggest that modulating the receptor interacting protein and its downstream targets may sensitize cancer cells to apoptosis when combined with cytotoxic chemotherapy.

Building on the tremendous strength in aerosol delivery and IND capability of  LRRI, a program has been initiated through partnership with the University of New Mexico and Johns Hopkins to develop aerosols for lung cancer treatment and prevention. Studies to encapsulate drugs with time release upon delivery are underway and aqueous formulation for delivery of the demethylating agent 5-azacytidine has been characterized and will be tested in an animal model.

 

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Steven Belinsky, PhD, co-leads the UNM Cancer Center’s Cancer Genetics, Epigenetics and Genomics Research Group with Mary Ann Osley, PhD. Learn more at: http://cancer.unm.edu/research/programs/cancer-genetics-epigenetics-genomics/