Pharmacogenomic Strategies Provide a Rational Approach to the Treatment of Cisplatin-Resistant Patients With Advanced Cancer

Hsu, David S.; Balakumaran, Bala S.; Acharya, Chaitanya R.; Vlahovic, Vanja; Walters, Kelli S.; Garman, Katherine S.; Anders, Carey K.; Riedel, Richard F.; Lancaster, Johnathan M.; Harpole, David H.; Dressman, Holly K.; Nevins, Joseph R.; Febbo, Phillip G.; Potti, Anil

doi:10.1200/jco.2007.11.0593

Cited by 95 publications

(80 citation statements)

References 25 publications

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“…Gene expression data obtained from cell lines transfected with each individual transcription factor were used to populate a matrix with MATLAB software. Statistical modeling representing activation of the individual transcription factors (NKX2-8, PAX9, and TTF-1) was performed using metagene construction and binary prediction analysis, as described previously (10,25,38). Gene expression signatures that reflect the activity of a given transcription factor were applied to a clinically annotated data set of 91 tumor samples (GSE3141) to predict patterns of transcription factor activation.…”

Section: Methodsmentioning

confidence: 99%

“…An estimated probability of 0.5 was classified as high probability of transcription factor activation and a probability of Ͻ0.5 was classified as low probability of transcription factor activation. Applications of the transcription factor predictors to other data sets (GSE4573, GSE3593) and the gene expression-based predictor of cisplatin resistance (38) to lung cancer cell lines and lung tumor data sets (GSE3141) were performed as described above. See SI Methods for complete details.…”

Section: Methodsmentioning

confidence: 99%

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Characterizing the developmental pathways TTF-1 , NKX2–8 , and PAX9 in lung cancer

Hsu

Acharya²,

Balakumaran³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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We investigated the clinical implications of lung developmental transcription factors ( TTF-1 , NKX2–8 , and PAX9 ) that we recently discovered as cooperating oncogenes activated by way of gene amplification at chromosome 14q13 in lung cancer. Using stable transfectants of human bronchial epithelial cells, RNA expression profiles (signatures) representing activation of the biological pathways defined by each of the 3 genes were determined and used to risk stratify a non-small-cell lung cancer (NSCLC) clinical data set consisting of 91 early stage tumors. Coactivation of the TTF-1 and NKX2–8 pathways identified a cluster of patients with poor survival, representing ≈20% of patients with early stage NSCLC, whereas activation of individual pathways did not reveal significant prognostic power. Importantly, the poor prognosis associated with coactivation of TTF-1 and NKX2–8 was validated in 2 other independent clinical data sets. Furthermore, lung cancer cell lines showing coactivation of the TTF-1 and NKX2–8 pathways were shown to exhibit resistance to cisplatin, the standard of care for the treatment of NSCLC. This suggests that the cohort of patients with coactivation of TTF-1 and NKX2–8 pathways appears to be resistant to standard cisplatin therapy, suggesting the need for alternative therapies in this cohort of high-risk patients.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Characterizing the developmental pathways TTF-1 , NKX2–8 , and PAX9 in lung cancer

Hsu

Acharya²,

Balakumaran³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Multidrug resistance is the major cause of chemotherapy failure in non-small cell lung cancer patients (24). The causes of MDR-induced chemotherapy failure are complex and may be determined by multiple tumour characteristics, such as the proportion of tumour cells that are not actively dividing, the adequacy of the tumour's blood supply, as well as the multidrug resistance phenotype (25).…”

Section: Discussionmentioning

confidence: 99%

“…resveratrol treatment, and the number of apoptotic cells increased in a time-and dose-dependent manner, with all resveratrol concentrations (25, 50, or100 μmol/l) inducing apoptosis at all time points (24,48, and 72 h) (Table IV).…”

Section: -------------------------------------------------mentioning

confidence: 99%

Resveratrol down-regulates survivin and induces apoptosis in human multidrug-resistant SPC-A-1/CDDP cells

Zhao

Bao²,

Qi³

et al. 2009

Oncol Rep

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Abstract.We studied the effect of resveratrol treatment on multidrug-resistant human non-small cell lung cancer cells. Human multidrug-resistant SPC-A-1/CDDP cells were treated with resveratrol at a concentration of 25, 50, or 100 μM in in vitro studies and nude mice were implanted with multidrug-resistant SPC-A-1/and fed a special diet that included resveratrol at a dose of either 1 g/kg/day or 3 g/kg/ day in in vivo studies. No adverse toxicological effects of resveratrol treatment were observed. The rate of cell proliferation, apoptosis ratio, cell cycle phase distribution, IC 50 values of cisplatin, gefitinib, and paclitaxel, implanted tumour volume, and expression of survivin in resveratrol-treated and control mice were then determined. Resveratrol significantly inhibited the proliferation of SPC-A-1/CDDP cells, induced apoptosis, arrested the cell cycle phase between G 0 -G 1 and S phase or at the G 2 /M phase, decreased the IC 50 values of multiple chemotherapeutic drugs, and showed anti-tumour effects in nude mice that had been implanted with SPC-A-1/ CDDP cells. In additional, resveratrol affected the proliferation of SPC-A-1/CDDP cells in a dose-and timedependent manner. Expression of survivin in SPC-A-1/CDDP cells decreased after they were treated with all concentrations of resveratrol and resveratrol was also found to have a dosedependent effect on survivin expression. Resveratrol can induce apoptosis in multidrug-resistant human NSCLC SPC-A-1/ CDDP cells by down-regulating the expression of survivin.

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“…Furthermore, in NSCLC, a genomic predictor for cisplatin sensitivity was found to have a better accuracy for predicting responders to cisplatin therapy than other conventional predictors. 58 The ability to predict sensitivity to commonly used chemotherapeutic agents is a necessary advance in the effective treatment of lung cancer. However, despite the very encouraging initial data, important ongoing prospective trials will confirm the actual feasibility and validity of an approach that uses genomic-based predictions of chemotherapeutic drug sensitivity.…”

Section: Expression Signatures Predicting Clinical Chemotherapy Responsementioning

confidence: 99%

Toward the individualization of lung cancer therapy

Anguiano

Nevins

Potti

2008

Cancer

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The goal of personalized cancer medicine is to effectively match the right treatment strategy with the patient. This includes an improvement of prognosis to identify which patients should be treated as well as the ability to predict which therapy will be most effective for the individual patient. Recent advances in the use of genomic technologies, primarily gene expression profiling with DNA microarrays, has provided mechanisms to address each of these questions. The prognosis of early-stage lung cancer patients (stage IA) is clearly imprecise because nearly 30% of these patients will develop disease recurrence (determined according to the TNM staging system). Gene expression profiles have been developed that can accurately predict recurrence and, when applied to the population of patients with stage IA disease, demonstrate a capacity to potentially identify those individuals likely to have been misclassified as low risk. In addition, gene expression information has also demonstrated an ability to predict who will respond to a particular chemotherapy regimen, providing a further opportunity to more effectively guide the selection of available therapies that best match the individual patient. Finally, other strategies offer the hope of better using the newly developed, experimental therapies that target specific components of the oncogenic process. Taken together, these new genomic tools provide the opportunity to develop rational strategies for treating the individual lung cancer patient.

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Pharmacogenomic Strategies Provide a Rational Approach to the Treatment of Cisplatin-Resistant Patients With Advanced Cancer

Abstract: The use of genomic predictors of response to cisplatin and pemetrexed can be incorporated into strategies to optimize therapy for advanced solid tumors.

Cited by 95 publications

References 25 publications

Characterizing the developmental pathways TTF-1 , NKX2–8 , and PAX9 in lung cancer

Characterizing the developmental pathways TTF-1 , NKX2–8 , and PAX9 in lung cancer

Resveratrol down-regulates survivin and induces apoptosis in human multidrug-resistant SPC-A-1/CDDP cells

Toward the individualization of lung cancer therapy

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