Assessing PIK3CA and PTEN in Early-Phase Trials with PI3K/AKT/mTOR Inhibitors

Janků, Filip; Hong, David S.; Fu, Siqing; Piha-Paul, Sarina A.; Naing, Aung; Falchook, Gerald S.; Tsimberidou, Apostolia M.; Stepanek, Vanda M.; Moulder, Stacy L.; Lee, John; Luthra, Rajyalakshmi; Zinner, Ralph; Broaddus, Russell R.; Wheler, Jennifer J.; Kurzrock, Razelle

doi:10.1016/j.celrep.2013.12.035

Cited by 219 publications

(208 citation statements)

References 44 publications

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“…Notwithstanding the fact that the TCGA Pan-Cancer study has focused exclusively on gene mutations, but not on gene amplification, the data are still conflicting with previous publications [47]. Nonetheless, ongoing clinical trials support the benefit of ovarian cancer patients from the pharmacological inhibition of the PI3K/AKT/mTOR pathway, therefore reinforcing the fact that solving ovarian cancer molecular profiling by means of characterizing the heterogeneity of its subtypes and their mutational landscape likely represents an opportunity to fight the disease using target therapies effective against specific aberrations [75][76][77].…”

Section: Ovarian Cancercontrasting

confidence: 49%

Metformin and mTOR Inhibitors: Allies against Ovarian and Breast Cancers

Guimarães¹,

Tessarollo²,

Santos³

et al. 2017

J Carcinog Mutagen

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Cancer is one of the leading causes of death worldwide. Every year 8.2 million people die from the disease. In this context, breast and ovarian cancer are the most incidental among women. Elucidation of cell growth pathways and the observation that these pathways are altered in human cancer have encouraged the search for specific inhibitors. The phosphatidylinositol-3cinase (PI3K)/Protein kinase b (AKT)/Mammalian Target of Rapamycin (mTOR) is an important pathway involved in cell growth, tumorigenesis, cell invasion, and resistance to therapies. This pathway is often activated in breast and ovarian cancers and the deregulation of its signaling can contribute to tumor growth, angiogenesis and metastasis. Metformin is one of the most commonly prescribed antidiabetic drugs in the world whose anticancer effects, mediated by reduced mTOR signaling, have become notable. Therefore, this review provides an overview of signaling pathway PI3K/AKT/mTOR in the ovarian and breast cancers as well as for target therapies of mTOR signaling, with an emphasis on its mechanisms, clinical applicability and future perspectives.

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Section: Ovarian Cancercontrasting

confidence: 49%

Metformin and mTOR Inhibitors: Allies against Ovarian and Breast Cancers

Guimarães¹,

Tessarollo²,

Santos³

et al. 2017

J Carcinog Mutagen

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“…The implication that combinations of matched therapy as opposed to monotherapy might have a stronger association with survival for patients with multiple molecular alterations (median ¼ 4 in our study), and that the number of alterations should be relevant to outcome should not be unexpected. Importantly in this regard, other studies have also suggested that patients treated with single-agent matched therapies had significantly lower responses rates than patients treated with combinations (41). Finally, overall, 87 of our 347 patients (25%) were matched to therapy on the basis of their genomic results.…”

Section: Discussionmentioning

confidence: 99%

Precision Oncology: The UC San Diego Moores Cancer Center PREDICT Experience

Schwaederlé¹,

Parker²,

Schwab³

et al. 2016

Molecular Cancer Therapeutics

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By profiling their patients' tumors, oncologists now have the option to use molecular results to match patients with drug(s) based on specific biomarkers. In this observational study, 347 patients with solid advanced cancers and next-generation sequencing (NGS) results were evaluated. Outcomes for patients who received a "matched" versus "unmatched" therapy following their NGS results were compared. Eighty-seven patients (25%) were treated with a "matched" therapy, 93 (26.8%) with an "unmatched" therapy. More patients in the matched group achieved stable disease (SD) ! 6 months/partial response (PR)/complete response (CR), 34.5% vs. 16.1%, (P 0.020 multivariable or propensity score methods). Matched patients had a longer median progression-free survival (PFS; 4.0 vs. 3.0 months, P ¼ 0.039 in the Cox regression model). In analysis using PFS1 (PFS on the prior line of therapy) as a comparator to PFS after NGS, as expected, the unmatched group demonstrated a PFS2 significantly shorter than PFS1 (P ¼ 0.009); however, this shortening was not observed in the matched patients (P ¼ 0.595). Furthermore, 45.3% of the matched patients (24/53) had a PFS2/ PFS1 ratio !1.3 compared with 19.3% of patients (11/57) in the unmatched group (P ¼ 0.004 univariable and P ! 0.057 in multivariable/propensity score analysis). Patients with a "matching-score" (the number of matched drugs divided by the number of aberrations; unmatched patients had a score of zero) > 0.2 had a median overall survival (OS) of 15.7 months compared with 10.6 months when their matching-score was 0.2, (P ¼ 0.040 in the Cox regression model). Matched versus unmatched patients had higher rates of SD ! 6 months/PR/CR and longer PFS, and improvement in OS correlated with a higher matching score in multivariable analysis. Mol Cancer Ther; 15(4); 743-52. Ó2016 AACR.

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“…Another perspective for this issue derives from studies showing that, in colorectal cancer patients, aberrations in the KRAS/BRAF axis often coexist with aberrations in the PI3K/AKT/mTOR axis (83)(84)(85), with each being a resistance pathway for the other (86,87). These co-mutations occur in other cancers as well, but not as frequently.…”

Section: Role Of the Pi3k/akt/mtor Axismentioning

confidence: 99%

Genomically Driven Tumors and Actionability across Histologies:BRAF-Mutant Cancers as a Paradigm

Turski¹,

Vidwans²,

Janků

et al. 2016

Molecular Cancer Therapeutics

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The diagnosis, classification, and management of cancer are traditionally dictated by the site of tumor origin, for example, breast or lung, and by specific histologic subtypes of site-oforigin cancers (e.g., non-small cell versus small cell lung cancer). However, with the advent of sequencing technologies allowing for rapid, low cost, and accurate sequencing of clinical samples, new observations suggest an expanded or different approach to the diagnosis and treatment of cancer-one driven by the unique molecular features of the tumor. We discuss a genomically driven strategy for cancer treatment using BRAF as an example. Several key points are highlighted: (i) molecular aberrations can be shared across cancers; (ii) approximately 15% of all cancers harbor BRAF mutations; and (iii) BRAF inhibitors, while approved only for melanoma, have reported activity across numerous cancers and related disease types bearing BRAF aberrations. However, BRAF-mutated colorectal cancer has shown poor response rate to BRAF inhibitor monotherapy, striking a cautionary note. Yet, even in this case, emerging data suggest BRAF-mutated colorectal cancers can respond well to BRAF inhibitors, albeit when administered in combination with other agents that impact resistance pathways. Taken together, these data suggest that molecular aberrations may be the basis for a new nosology for cancer. Mol Cancer Ther; 15(4); 533-47. Ó2016 AACR.

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Assessing PIK3CA and PTEN in Early-Phase Trials with PI3K/AKT/mTOR Inhibitors

Cited by 219 publications

References 44 publications

Metformin and mTOR Inhibitors: Allies against Ovarian and Breast Cancers

Metformin and mTOR Inhibitors: Allies against Ovarian and Breast Cancers

Precision Oncology: The UC San Diego Moores Cancer Center PREDICT Experience

Genomically Driven Tumors and Actionability across Histologies:BRAF-Mutant Cancers as a Paradigm

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