Impact of Genomics on Personalized Cancer Medicine

Arteaga, Carlos L.; Baselga, José

doi:10.1158/1078-0432.ccr-11-2019

Cited by 53 publications

(53 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The treatment of many solid tumors has shifted toward a "personalized approach" where tumor-specifi c molecular abnormalities are targeted with appropriately matched pharmacologic inhibitors ( 5 ). However, to identify clinically relevant molecular targets, one must use appropriate profi ling techniques.…”

Section: B R C a 2 B R A F T P 5 3 S M A D 4 C D K N 2 A C D K N 2 B mentioning

confidence: 99%

“…Median overall survival (14-38 months) is improved with surgical resection, but few patients achieve durable responses from chemotherapy and/or radiotherapy ( 1 , 4 ). Unlike other solid tumors in which targeted therapies against matched molecular aberrations have proven superior to chemotherapy ( 5 ), few such targets have been identifi ed in PACC. Studies investigating the genomics of PACC have observed activation of the β-catenin pathway, broad chromosomal gains and losses encompassing multiple genes, and somatic inactivation of tumor-suppressor genes (e.g., SMAD4 , RB1 , BRCA2 , and TP53 ; refs.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Comprehensive Genomic Profiling of Pancreatic Acinar Cell Carcinomas Identifies Recurrent RAF Fusions and Frequent Inactivation of DNA Repair Genes

et al. 2014

View full text Add to dashboard Cite

Pancreatic acinar cell carcinomas (PACC) account for approximately 1% (∼500 cases) of pancreatic cancer diagnoses annually in the United States. Oncogenic therapuetic targets have proven elusive in this disease, and chemotherapy and radiotherapy have demonstrated limited effi cacy against these tumors. Comprehensive genomic profi ling of a large series of PACCs ( n = 44) identifi ed recurrent rearrangements involving BRAF and RAF1 ( CRAF ) in approximately 23% of tumors. The most prevalent fusion, SND1-BRAF , resulted in activation of the MAPK pathway, which was abrogated with MEK inhibition. SND1-BRAF -transformed cells were sensitive to treatment with the MEK inhibitor trametinib. PACCs lacking RAF rearrangements were signifi cantly enriched for genomic alterations, causing inactivation of DNA repair genes (45%); these genomic alterations have been associated with sensitivity to platinum-based therapies and PARP inhibitors. Collectively, these results identify potentially actionable genomic alterations in the majority of PACCs and provide a rationale for using personalized therapies in this disease. SIGNIFICANCE:PACC is genomically distinct from other pancreatic cancers. Fusions in RAF genes and mutually exclusive inactivation of DNA repair genes represent novel potential therapeutic targets that are altered in over two thirds of these tumors.

show abstract

Section: B R C a 2 B R A F T P 5 3 S M A D 4 C D K N 2 A C D K N 2 B mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Comprehensive Genomic Profiling of Pancreatic Acinar Cell Carcinomas Identifies Recurrent RAF Fusions and Frequent Inactivation of DNA Repair Genes

et al. 2014

View full text Add to dashboard Cite

show abstract

“…While it is known that the functional inactivation of pRB causes major changes, beyond the fact that these cells are more easily driven into the cell cycle, we currently understand very little about the range of cellular processes that are altered when pRB is lost. A major initiative in cancer research is the idea of personalized medicine and the use of treatments that are tailored to the unique properties of each tumor (Haber et al 2011;Arteaga and Baselga 2012). This concept relies on the idea that changes in specific oncogenes/tumor suppressor genes generate unique dependencies that can be exploited.…”

mentioning

confidence: 99%

Loss of RBF1 changes glutamine catabolism

et al. 2013

View full text Add to dashboard Cite

Inactivation of the retinoblastoma tumor suppressor (pRB) alters the expression of a myriad of genes. To understand the altered cellular environment that these changes create, we took advantage of the Drosophila model system and used targeted liquid chromatography tandem mass spectrometry (LC-MS/MS) to profile the metabolic changes that occur when RBF1, the fly ortholog of pRB, is removed. We show that RBF1-depleted tissues and larvae are sensitive to fasting. Depletion of RBF1 causes major changes in nucleotide synthesis and glutathione metabolism. Under fasting conditions, these changes interconnect, and the increased replication demand of RBF1-depleted larvae is associated with the depletion of glutathione pools. In vivo 13 C isotopic tracer analysis shows that RBF1-depleted larvae increase the flux of glutamine toward glutathione synthesis, presumably to minimize oxidative stress. Concordantly, H 2 O 2 preferentially promoted apoptosis in RBF1-depleted tissues, and the sensitivity of RBF1-depleted animals to fasting was specifically suppressed by either a glutamine supplement or the antioxidant N-acetyl-cysteine. Effects of pRB activation/inactivation on glutamine catabolism were also detected in human cell lines. These results show that the inactivation of RB proteins causes metabolic reprogramming and that these consequences of RBF/RB function are present in both flies and human cell lines.

show abstract

“…Indeed, other investigators have shown that specific molecular testing for these aberrations and use of agents to target these aberrations is associated with improved clinical outcomes (8,10,(28)(29)(30)(31)(32)(33)(34). For instance, the use of BRAF inhibitors in patients with BRAF-mutated melanoma and ALK inhibitors in patients with ALK-rearranged lung cancer (6) showed remarkably high response rates, even in the phase I setting.…”

Section: Discussionmentioning

confidence: 99%

Personalized medicine in a phase I clinical trials program: The M. D. Anderson Cancer Center Initiative.

Tsimberidou¹,

Iskander²,

Hong³

et al. 2011

JCO

View full text Add to dashboard Cite

Purpose-We initiated a personalized medicine program in the context of early clinical trials, using targeted agents matched with tumor molecular aberrations. Herein, we report our observations. Patient and Methods-Patients HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptResults-Of 1,144 patients analyzed, 460 (40.2%) had 1 or more aberration. In patients with 1 molecular aberration, matched therapy (n = 175) compared with treatment without matching (n = 116) was associated with a higher overall response rate (27% vs. 5%; P < 0.0001), longer time-totreatment failure (TTF; median, 5.2 vs. 2.2 months; P< 0.0001), and longer survival (median, 13.4 vs. 9.0 months; P= 0.017). Matched targeted therapy was associated with longer TTF compared with their prior systemic therapy in patients with 1 mutation (5.2 vs. 3.1 months, respectively; P < 0.0001). In multivariate analysis in patients with 1 molecular aberration, matched therapy was an independent factor predicting response (P = 0.001) and TTF (P = 0.0001).Conclusion-Keeping in mind that the study was not randomized and patients had diverse tumor types and a median of 5 prior therapies, our results suggest that identifying specific molecular abnormalities and choosing therapy based on these abnormalities is relevant in phase I clinical trials.

show abstract

Impact of Genomics on Personalized Cancer Medicine

Cited by 53 publications

References 51 publications

Comprehensive Genomic Profiling of Pancreatic Acinar Cell Carcinomas Identifies Recurrent RAF Fusions and Frequent Inactivation of DNA Repair Genes

Comprehensive Genomic Profiling of Pancreatic Acinar Cell Carcinomas Identifies Recurrent RAF Fusions and Frequent Inactivation of DNA Repair Genes

Loss of RBF1 changes glutamine catabolism

Personalized medicine in a phase I clinical trials program: The M. D. Anderson Cancer Center Initiative.

Contact Info

Product

Resources

About