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HER2+ Cancer Cell Dependence on PI3K vs. MAPK Signaling Axes Is Determined by Expression of EGFR, ERBB3 and CDKN1B.

Understanding the molecular pathways by which oncogenes drive cancerous cell growth, and how dependence on such pathways varies between tumors could be highly valuable for the design of anti-cancer treatment strategies. In this work we study how dependence upon the canonical PI3K and MAPK cascades varies across HER2+ cancers, and define biomarkers predictive of pathway dependencies. A panel of 18 HER2+ (ERBB2-amplified) cell lines representing a variety of indications was used to characterize the functional and molecular diversity within this oncogene-defined cancer. PI3K and MAPK-pathway dependencies were quantified by measuring in vitro cell growth responses to combinations of AKT (MK2206) and MEK (GSK1120212; trametinib) inhibitors, in the presence and absence of the ERBB3 ligand heregulin (NRG1). A combination of three protein measurements comprising the receptors EGFR, ERBB3 (HER3), and the cyclin-dependent kinase inhibitor p27 (CDKN1B) was found to accurately predict dependence on PI3K/AKT vs. MAPK/ERK signaling axes. Notably, this multivariate classifier outperformed the more intuitive and clinically employed metrics, such as expression of phospho-AKT and phospho-ERK, and PI3K pathway mutations (PIK3CA, PTEN, and PIK3R1). In both cell lines and primary patient samples, we observed consistent expression patterns of these biomarkers varies by cancer indication, such that ERBB3 and CDKN1B expression are relatively high in breast tumors while EGFR expression is relatively high in other indications. The predictability of the three protein biomarkers for differentiating PI3K/AKT vs. MAPK dependence in HER2+ cancers was confirmed using external datasets (Project Achilles and GDSC), again out-performing clinically used genetic markers. Measurement of this minimal set of three protein biomarkers could thus inform treatment, and predict mechanisms of drug resistance in HER2+ cancers. More generally, our results show a single oncogenic transformation can have differing effects on cell signaling and growth, contingent upon the molecular and cellular context.

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In1-ghrelin splicing variant is overexpressed in pituitary adenomas and increases their aggressive features.

Pituitary adenomas comprise a heterogeneous subset of pathologies causing serious comorbidities, which would benefit from identification of novel, common molecular/cellular biomarkers and therapeutic targets. The ghrelin system has been linked to development of certain endocrine-related cancers. Systematic analysis of the presence and functional implications of some components of the ghrelin system, including native ghrelin, receptors and the recently discovered splicing variant In1-ghrelin, in human normal pituitaries (n = 11) and pituitary adenomas (n = 169) revealed that expression pattern of ghrelin system suffers a clear alteration in pituitary adenomasas compared with normal pituitary, where In1-ghrelin is markedly overexpressed. Interestingly, in cultured pituitary adenoma cells In1-ghrelin treatment (acylated peptides at 100 nM; 24-72 h) increased GH and ACTH secretion, Ca(2+) and ERK1/2 signaling and cell viability, whereas In1-ghrelin silencing (using a specific siRNA; 100 nM) reduced cell viability. These results indicate that an alteration of the ghrelin system, specially its In1-ghrelin variant, could contribute to pathogenesis of different pituitary adenomas types, and suggest that this variant and its related ghrelin system could provide new tools to identify novel, more general diagnostic, prognostic and potential therapeutic targets in pituitary tumors.

Comprehensive Genomic Profiling of Carcinoma of Unknown Primary Site: New Routes to Targeted Therapies.

For carcinoma of unknown primary site (CUP), determining the primary tumor site may be uninformative and often does not improve outcome.
To discover opportunities for targeted therapies in patients with CUP not currently searched for in routine practice.
Comprehensive genomic profiling on 200 CUP formalin-fixed paraffin-embedded specimens (mean, 756× coverage) using the hybrid-capture-based FoundationOne assay at academic and community oncology clinics.
Presence of targetable genomic alterations (GAs) in CUP and responses to targeted therapies.
There were 125 adenocarcinomas of unknown primary site (ACUPs) and 75 carcinomas of unknown primary site without features of adenocarcinoma (non-ACUPs). At least 1 GA was found in 192 (96%) of CUP specimens, with a mean (SD) of 4.2 (2.8) GAs per tumor. The most frequent GAs were in TP53 (110 [55%]), KRAS (40 [20%]), CDKN2A (37 [19%]), MYC (23 [12%]), ARID1A (21 [11%]), MCL1 (19 [10%]), PIK3CA (17 [9%]), ERBB2 (16 [8%]), PTEN (14 [7%]), EGFR (12 [6%]), SMAD4 (13 [7%]), STK11 (13 [7%]), SMARCA4 (12 [6%]), RB1 (12 [6%]), RICTOR (12 [6%]), MLL2 (12 [6%]), BRAF (11 [6%]), and BRCA2 (11 [6%]). One or more potentially targetable GAs were identified in 169 of 200 (85%) CUP specimens. Mutations or amplifications of ERBB2 were more frequent in ACUPs (13 [10%]) than in non-ACUPs (3 [4%]). Alterations of EGFR (10 [8%] vs 2 [3%]) and BRAF (8 [6%] vs 3 [4%]) were more common in ACUPs than in non-ACUPs. Strikingly, clinically relevant alterations in the receptor tyrosine kinase (RTK)/Ras signaling pathway including alterations in ALK, ARAF, BRAF, EGFR, FGFR1, FGFR2, KIT, KRAS, MAP2K1, MET, NF1, NF2, NRAS, RAF1, RET, and ROS1 were found in 90 (72%) ACUPs but in only 29 (39%) non-ACUPs (P &lt; .001).
Almost all CUP samples harbored at least 1 clinically relevant GA with potential to influence and personalize therapy. The ACUP tumors were more frequently driven by GAs in the highly druggable RTK/Ras/mitogen-activated protein kinase (MAPK) signaling pathway than the non-ACUP tumors. Comprehensive genomic profiling can identify novel treatment paradigms to address the limited options and poor prognoses of patients with CUP.

Degarelix monotherapy compared with luteinizing hormone-releasing hormone (LHRH) agonists plus anti-androgen flare protection in advanced prostate cancer: an analysis of two randomized controlled trials.

The objective of this study was to assess differences in efficacy outcomes between luteinizing hormone-releasing hormone (LHRH) agonist plus antiandrogen (AA) flare protection and monotherapy with the gonadotrophin-releasing hormone antagonist degarelix in patients with prostate cancer.
Data from 1455 patients were pooled from two prospective, phase III randomized 1-year clinical trials of degarelix versus LHRH agonist with or without AA. The AA bicalutamide was administered at the investigator’s discretion. Adjusted hazard ratios (HRs) were calculated using a Cox proportional hazards regression model and a conditional logistic regression model was used for a case-control analysis of odds ratios (ORs).
Patients received degarelix monotherapy (n = 972) or LHRH agonist (n = 483) of whom 57 also received AA. Overall, prostate-specific antigen progression-free survival (PSA PFS) was improved with degarelix versus LHRH agonist + AA (Cox proportional hazards regression model-adjusted HR for PSA PFS failure was 0.56 [95% confidence interval (CI) 0.33-0.97, p = 0.038]). To compensate for a higher proportion of patients with metastases, Gleason score 7-10, and PSA &gt;20 ng/ml in the LHRH agonist + AA group, a case-control analysis using a conditional logistic regression model was utilized. This resulted in an OR for PSA PFS of 0.42 (95% CI 0.20-0.89; p = 0.023) in the overall population, and 0.35 (95% CI 0.13-0.96; p = 0.042) in patients with PSA &gt;50 ng/ml at baseline, when treated with degarelix versus LHRH agonists + AA. There were a small number of deaths, 1.9% with degarelix and 7% with LHRH agonists + AA (case-control analysis OR = 0.37; p = 0.085).
Degarelix monotherapy produced a more favorable effect on PSA PFS outcomes than a LHRH agonist + AA flare protection therapy in patients with prostate cancer when a case-control analysis was used to compensate for differences between treatment groups.

Patient and caregiver awareness of pancreatic cancer treatments and clinical trials.

The poor prognosis of pancreatic cancer has been well established. For many patients, active treatments can improve patient outcomes, such as overall survival and symptom control. Nevertheless, there is evidence that pancreatic cancer is undertreated, even in patients with resectable disease. In addition, although participation in a clinical trial is recommended by current pancreatic cancer treatment guidelines, recent data suggest that patient participation in ongoing trials is below overall target accrual.
A survey was prepared and distributed to patients with pancreatic cancer and caregivers of patients with pancreatic cancer by the Pancreatic Cancer Action Network (funding for the survey was provided by Celgene Corporation). The 70-question survey was completed between July 30, 2013, and September 18, 2013, by respondents in the United States. The goal of this analysis was to evaluate patient and caregiver interactions with physicians about pancreatic cancer treatments and participation in clinical trials.
The survey was completed by 184 patients and 213 caregivers (not necessarily paired). Quality of life, extension of survival, and symptom management were identified as the most important concerns among both patients and caregivers. A large majority of respondents (94.9%) reported that the patient followed the physician’s treatment recommendation. Approximately 30% of respondents indicated that the diagnosing physician offered treatment options at the time of diagnosis. Among the respondents who indicated that the physician did not offer treatment options at diagnosis, 20.4% stated that no doctor had ever spoken to them about treatment options. Most respondents (83.1%) reported that the patient received chemotherapy for pancreatic cancer. Approximately half of respondents (49.1%) indicated that they had never discussed clinical trials with a physician. Twelve percent of respondents reported that the patient participated in a clinical trial. In those cases, physicians were listed as the primary source of trial information 80.4% of the time. Familiarity with Patient Central (known as &quot;Patient and Liaison Services&quot; at the time of the study), a support service offered by the Pancreatic Cancer Action Network, was associated with higher rates of receiving treatment (P&lt;0.05), searching the Internet for information on clinical trials (P&lt;0.05), and participating in clinical trials (not statistically significant).
The results of this study suggest that large numbers of patients and caregivers had never had discussions with physicians about pancreatic cancer treatments or clinical trials. The point about trials takes on even greater importance, considering that patients who participate in clinical trials report better outcomes than those receiving the same treatment outside of clinical trials. Increased discussions with patients could potentially increase treatment and trial participation, possibly improving patient- and caregiver-stated priorities of quality of life, extension of survival, and symptom management.