Identification of novel therapeutic targets in the PI3K/AKT/mTOR pathway in hepatocellular carcinoma using targeted next generation sequencing.

Understanding genetic aberrations in cancer leads to discovery of new targets for cancer therapies. The genomic landscape of hepatocellular carcinoma (HCC) has not been fully described. Therefore, patients with refractory advanced/metastatic HCC referred for experimental therapies, who had adequate tumor tissue available, had targeted next generation sequencing (NGS) of their tumor samples using the Illumina HiSeq 2000 platform (Foundation One, Foundation Medicine, MA) and their treatment outcomes were analyzed. In total, NGS was obtained for 14 patients (median number of prior therapies, 1) with advanced/metastatic HCC. Of these 14 patients, 10 (71%) were men, 4 (29%) women, 6 (43%) had hepatitis B or C-related HCC. NGS revealed at least 1 molecular abnormality in 12 patients (range 0-8, median 2). Detected molecular aberrations led to putative activation of the PI3K/AKT/mTOR pathway (n=3 [mTOR, PIK3CA, NF1]), Wnt pathway (n=6 [CTNNA1, CTNNB1]), MAPK pathway (n=2 [MAP2K1, NRAS]), and aberrant DNA repair mechanisms, cell cycle control and apoptosis (n=18 [ATM, ATR, BAP1, CCND1, CDKN2A, CDK4, FGF3, FGF4, FGF19, MCL1, MDM2, RB1, TP53]). Of the 3 patients with molecular aberrations putatively activating the PI3K/AKT/mTOR pathway, 2 received therapies including a mTOR inhibitor and all demonstrated therapeutic benefit ranging from a partial response to minor shrinkage per RECIST (-30%, -15%; respectively). In conclusion, genomic alterations are common in advanced HCC. Refractory patients with alterations putatively activating the PI3K/AKT/mTOR pathway demonstrated early signals of clinical activity when treated with therapies targeting mTOR

A pilot study of temsirolimus and body composition.

PurposeBody weight and composition play a role in cancer etiology, prognosis, and treatment response. Therefore, we analyzed the weight, body composition changes, and outcome in patients treated with temsirolimus, an mTor inhibitor that has weight loss as one of its side effects.Patients and methodsSixteen patients with advanced solid tumors treated with temsirolimus were studied; body composition was evaluated utilizing computerized tomography images. Sarcopenia was defined as skeletal muscle index lower than 38.5 cm(2)/m(2) for women and 52.4 cm(2)/m(2) for men.ResultsFive of 16 patients (31 %) were men; median age, 60 years. Forty-four percent (7/16) of patients were sarcopenic. Fatigue, anemia, hyperglycemia, and hyperlipidemia were common. Baseline sarcopenia and body composition did not correlate with worse toxicity or treatment outcome. However, there was a trend for greater loss of adipose area (p = 0.07), fat mass (p = 0.09), and adipose index (p = 0.07) for patients with grade 3 or 4 toxicities versus those with grade 1 and 2 side effects.ConclusionPatients with higher grade toxicities tended to lose more body fat, suggesting a possible end-organ metabolic effect of temsirolimus. These observations merit exploration in a larger cohort of patients

Advanced gynecologic malignancies treated with a combination of the VEGF inhibitor bevacizumab and the mTOR inhibitor temsirolimus.

BackgroundBevacizumab and temsirolimus are active agents in gynecologic tumors. Temsirolimus attenuates upregulation of HIF-1α levels, a resistance mechanism for antiangiogenics, and targets the PI3-kinase/AKT/mTOR axis, commonly aberrant in these tumors.Patients and methodsWe analyzed safety and responses in 41 patients with gynecologic cancers treated as part of a Phase I study of bevacizumab and temsirolimus.ResultsMedian age of the 41 women was 60 years (range, 33-80 years); median number of prior systemic therapies was 4 (1-11). Grade 3 or 4 treatment-related toxicities included: thrombocytopenia (10%), mucositis (2%), hypertension (2%), hypercholesterolemia (2%), fatigue (7%), elevated aspartate aminotransferase (2%), and neutropenia (2%). Twenty-nine patients (71%) experienced no treatment-related toxicity greater than grade 2. Full FDA-approved doses of both drugs (bevacizumab 15mg/kg IV Q3weeks and temsirolimus 25mg IV weekly) were administered without dose-limiting toxicity. Eight patients (20%) achieved stable disease (SD) > 6 months and 7 patients (17%), a partial response (PR) [total = 15/41 patients (37%)]. Eight of 13 patients (62%) with high-grade serous histology (ovarian or primary peritoneal) achieved SD > 6 months/PR.ConclusionBevacizumab and temsirolimus was well tolerated. Thirty-seven percent of heavily-pretreated patients achieved SD > 6 months/PR, suggesting that this combination warrants further study

Characteristics and survival of patients with advanced cancer and p53 mutations.

P53 mutations are associated with invasive tumors in mouse models. We assessed the p53mutations and survival in patients with advanced cancer treated in the Phase I Program. Of 691 tested patients, 273 (39.5%) had p53 mutations. Patients with p53 mutations were older (p<.0001) and had higher numbers of liver metastases (p=.005). P53 mutations were associated with higher numbers of other aberrations; PTEN (p=.0005) and HER2 (p=.003)aberrations were more common in the p53 mutation group. No survival difference was observed between patients with p53 mutations and those with wild-type p53. In patients with wild-type p53 and other aberrations, patients treated with matched-therapy against the additional aberrations had longer survival compared to those treated with non-matched-therapy or those who received no therapy (median survival, 26.0 vs. 11.8 vs. 9.8 months, respectively; p= .0007). Results were confirmed in a multivariate analysis (p= .0002). In the p53 mutation group with additional aberrations, those who received matched-therapy against the additional aberrations had survival similar to those treated with non-matched-therapy or those who received no therapy (p=.15). In conclusion, our results demonstrated resistance to matched-targeted therapy to the other aberrations in patients with p53 mutations and emphasize the need to overcome this resistance

Phase 1 dose escalation study of the allosteric AKT inhibitor BAY 1125976 in advanced solid cancer-Lack of association between activating AKT mutation and AKT inhibition-derived efficacy

This open-label, phase I first-in-human study (NCT01915576) of BAY 1125976, a highly specific and potent allosteric inhibitor of AKT1/2, aimed to evaluate the safety, pharmacokinetics, and maximum tolerated dose of BAY 1125976 in patients with advanced solid tumors. Oral dose escalation was investigated with a continuous once daily (QD) treatment (21 days/cycle) and a twice daily (BID) schedule. A dose expansion in 28 patients with hormone receptor-positive metastatic breast cancer, including nine patients harboring th

Dual EGFR inhibition in combination with anti-VEGF treatment: a phase I clinical trial in non-small cell lung cancer.

BackgroundPreclinical data indicate EGFR signals through both kinase-dependent and independent pathways and that combining a small-molecule EGFR inhibitor, EGFR antibody, and/or anti-angiogenic agent is synergistic in animal models.MethodsWe conducted a dose-escalation, phase I study combining erlotinib, cetuximab, and bevacizumab. The subset of patients with non-small cell lung cancer (NSCLC) was analyzed for safety and response.ResultsThirty-four patients with NSCLC (median four prior therapies) received treatment on a range of dose levels. The most common treatment-related grade ≥2 adverse events were rash (n=14, 41%), hypomagnesemia (n=9, 27%), and fatigue (n=5, 15%). Seven patients (21%) achieved stable disease (SD) ≥6 months, two achieved a partial response (PR) (6%), and two achieved an unconfirmed partial response (uPR) (6%) (total=32%). We observed SD≥6 months/PR/uPR in patients who had received prior erlotinib and/or bevacizumab, those with brain metastases, smokers, and patients treated at lower dose levels. Five of 16 patients (31%) with wild-type EGFR experienced SD≥6 months or uPR. Correlation between grade of rash and rate of SD≥6 months/PR was observed (p less than 0.01).ConclusionThe combination of erlotinib, cetuximab, and bevacizumab was well-tolerated and demonstrated antitumor activity in heavily pretreated patients with NSCLC

Dual EGFR inhibition in combination with anti-VEGF treatment in colorectal cancer.

Preclinical studies demonstrate that epidermal growth factor receptor (EGFR) signals through both kinase-dependent and independent pathways and that combining a small-molecule EGFR inhibitor, EGFR antibody, and/or anti-angiogenic agent is synergistic. We conducted a dose-escalation, phase I study combining erlotinib, cetuximab, and bevacizumab. The subset of patients with metastatic colorectal cancer was analyzed for safety and antitumor activity. Forty-one patients with heavily pretreated metastatic colorectal cancer received treatment on a range of dose levels. The most common treatment-related grade ≥2 adverse events were rash (68%), hypomagnesemia (37%), and fatigue (15%). Thirty of 34 patients (88%) treated at the full FDA-approved doses of all three drugs tolerated treatment without drug-related dose-limiting effects. Eleven patients (27%) achieved stable disease (SD) ≥6 months and three (7%) achieved a partial response (PR) (total SD>6 months/PR= 14 (34%)). Of the 14 patients with SD≥6 months/PR, eight (57%) had received prior sequential bevacizumab and cetuximab, two (5%) had received bevacizumab and cetuximab concurrently, and four (29%) had received prior bevacizumab but not cetuximab or erlotinib (though three had received prior panitumumab). The combination of bevacizumab, cetuximab, and erlotinib was well tolerated and demonstrated antitumor activity in heavily pretreated patients with metastatic colorectal cancer

PIK3CA mutations in advanced cancers: characteristics and outcomes.

PIK3CA mutations are frequently diagnosed in diverse cancers and may predict response to PI3K/AKT/mTOR inhibitors. It remains unclear whether they are associated with other characteristics. We analyzed characteristics and outcome of 90 consecutive patients with diverse advanced tumors and PIK3CA mutations and 180 wild-type PIK3CA controls matched by tumor type, gender, and age referred to the Clinical Center for Targeted Therapy. PIK3CA and MAPK mutations (KRAS, NRAS, and BRAF) were analyzed using polymerase chain reaction-based DNA sequencing. The most frequent PIK3CA mutations were E545K (31/90, 34%), E542K (16/90, 18%) in exon 9, and H1047R (20/90, 22%) in exon 20. PIK3CA mutations compared to wild-type PIK3CA were associated with simultaneous KRAS (p=0.047) and MAPK mutations (p=0.03), but only MAPK mutations were confirmed as having an independent association in multivariate analysis. Rates of lung, bone, liver and brain metastases were similar in PIK3CA-mutant and wild-type patients. Patients with PIK3CA mutations treated on trials with PI3K/AKT/mTOR inhibitors had a higher partial/complete response (PR/CR) rate than wild-type PIK3CA patients treated with their best phase I therapy (10/56, 18% vs. 12/152, 8%; p=0.045), but not a prolonged progression-free survival. Patients with H1047R PIK3CA mutations had higher PR/CR rate with PI3K/AKT/mTOR inhibitors compared to wild-type PIK3CA patients treated with their best phase I therapy (6/16, 38% vs. 12/152, 8%; p=0.003). In conclusion, PIK3CA mutations in diverse cancers were not associated with clinical characteristics, but were correlated with MAPK mutations. PIK3CA mutations, especially, H1047R, were associated with attaining a PR/CR to PI3K/AKT/mTOR pathway inhibitors

Targeted therapy of advanced gallbladder cancer and cholangiocarcinoma with aggressive biology: eliciting early response signals from phase 1 trials.

PurposePatients with advanced cholangiocarcinoma (CC) and gallbladder carcinoma (GC) have few therapeutic options for relapsed disease. methods: Given the overall poor prognosis in this population and the availability of novel targeted therapies, we systematically analyzed the characteristics and outcomes for GC and CC patients treated on phase I trials with an emphasis on targeted agents and locoregional therapies.ResultsOf 40 treated patients (GC=6; CC=34; median age, 60 years), 8 (20%) had stable disease (SD) > 6 months, 3 (8%) partial response (PR), on protocols with hepatic arterial drug infusion and anti-angiogenic, anti-HER-2/neu or novel MAPK/ERK kinase (MEK) inhibitors. Median progression-free survival (PFS) on phase I trials was 2.0 months (95% CI 1.7, 2.8) versus 3.0 months (95% CI 2.4, 5.0), 3.0 months (95% CI 2.3, 4.6), and 3.0 months (95% CI 2.4, 3.9) for their first-, second-, and last-line FDA-approved therapy. In univariate analysis, >3 metastatic sites, elevated alanine aminotransferase (ALT) (>56IU/L), serum creatinine (>1.6mg/dL), and CA19-9 (>35U/mL) were associated with a shorter PFS. Mutational analysis revealed mutation in the KRAS oncogene in 2 of 11 patients (18%). The SD >6 months/PR rate of 28% was seen with hepatic arterial infusion of oxaliplatin, and inhibitors of angiogenesis, HER-2/neu or MEK.ConclusionsThe PFS in phase I trials was similar to that of the first, second, and last-line therapy (P=0.95, 0.98, 0.76, respectively) with FDA-approved agents given in the advanced setting, emphasizing a role for targeted agents in a clinical trials setting as potentially valuable therapeutic options for these patients