Angelica Fasolo

mTOR inhibitors in the treatment of cancer

Background: The mammalian target of rapamycin (mTOR) is a protein kinase of the phosphatidylinositol 3-kinase (PI3K)/Akt signalling pathway with a central role in the control of cell proliferation, survival, mobility and angiogenesis. Dysregulation of mTOR pathway has been found in many human tumours; therefore, the mTOR pathway is considered an important target for the development of new anticancer drugs. Objective: To review the mTOR pathway, the role of the mTOR inhibitors in cancer treatment, the preclinical features and clinical results of the three mTOR inhibitors currently in development, temsirolimus, everolimus and deforolimus. Methods: Review of the published literature (abstracts, full papers) since 1995 on mTOR pathway and related pathway signalling, rapamycin and analogues. Results/conclusion: With each of the three mTOR inhibitors temsirolimus (CCI-779), everolimus (RAD001) and deforolimus (AP23573), a safe schedule of treatment has been defined and promising results of antitumour activity have been achieved in a variety of solid tumours, thus confirming the preclinical expectations.

Targeting mTOR pathways in human malignancies.

BACKGROUND The mammalian target of rapamycin (mTOR) is a protein kinase involved in the phosphatidylinositol 3-Kinase (PI3K)/AKT signalling pathway with a central role in the control of cell growth, survival and angiogenesis. Multiple and frequent dysregulations of this pathway in human tumors make it a central target in the development of new anticancer treatments. OBJECTIVE To review the most significant data on mTOR pathway, role of mTOR inhibitors in cancer treatment, preclinical and clinical data of the three first generation mTOR inhibitors (temsirolimus, everolimus and deferolimus), rationales, preclinical and clinical data of second generation mTOR inhibitors. METHODS Review of published literature on mTOR and related pathways, rapalogs and novel mTOR inhibitors. RESULTS/CONCLUSIONS Temsirolimus and everolimus have been approved for the treatment of metastatic Renal Cell Carcinoma (RCC), temsirolimus also for Mantle Cell Lymphoma (MCL) and everolimus will be approved for pancreatic neuroendocrine tumors; all three rapalogs are currently evaluated in phase III studies in several tumors. Only limited published data are available on new mTOR inhibitors; however, in vitro and in vivo in preclinical studies they have shown a significant antiproliferative activity against a broad panel of tumors and a favourable safety profile, with disease stabilization or even tumor regression, either as single agent or in combination.

Trastuzumab as adjuvant systemic therapy for HER2-positive breast cancer.

Trastuzumab has an established role for the treatment of HER2-positive early-stage breast cancer because of the success of this agent in the adjuvant setting. Several key questions about the value of trastuzumab for the treatment of breast cancer, however, still need to be answered. Various differences in patient characteristics and treatment regimens were present in the randomized trials discussed in this Review; therefore, the details of trastuzumab use need clarification. For example, the optimum timing, the ideal administration schedule, and the appropriate length of treatment are not known. Cardiotoxicity is major concern even though the results of all randomized trials have shown that the degree of cardiotoxicity with trastuzumab is acceptable—the incidence of cardiac damage caused by trastuzumab ranged from 0.4% to 4.1% in the different trials (cumulative incidence of congestive heart failure, New York Heart Association class 3–4). Current data do not support the use of trastuzumab for more than 1 year. The analysis of 2-year treatment with trastuzumab is expected to be available in 2009.

Phase I study of olaparib in combination with liposomal doxorubicin in patients with advanced solid tumours.

Background:Olaparib, an oral PARP inhibitor, has shown antitumour activity as monotherapy in patients with germline BRCA1/2 (gBRCA)-mutated breast and ovarian cancer. This study evaluated olaparib capsules in combination with liposomal doxorubicin (PLD) in patients with advanced solid tumours (NCT00819221).Methods:Patients received 28-day cycles of olaparib, continuously (days 1–28) or intermittently (days 1–7), plus PLD (40 mg m−2, day 1); seven olaparib dose cohorts (50–400 mg bid) were explored to determine the recommended dose. Assessments included safety, pharmacokinetics, pharmacodynamics and preliminary efficacy (objective response rate (ORR)).Results:Of 44 patients treated (ovarian, n=28; breast, n=13; other/unknown, n=3), two experienced dose-limiting toxicities (grade 3 stomatitis and fatal pneumonia/pneumonitis (200 mg per 28-day cycle); grade 4 thrombocytopenia (400 mg per 7-day cycle)). The maximum tolerated dose was not reached using continuous olaparib 400 mg bid plus PLD. Grade ⩾3 and serious AEs were reported for 27 (61%) and 12 (27%) patients, respectively. No major pharmacokinetic interference was observed between olaparib and PLD. The ORR was 33% (n=14 out of 42; complete response, n=3). A total of 13 responders had ovarian cancer: 10 were platinum-sensitive, 11 had a gBRCA mutation.Conclusions:Continuous/intermittent olaparib (up to 400 mg bid) combined with PLD (40 mg m−2) was generally tolerated and showed evidence of antitumour activity in ovarian cancer.

Clinical and pharmacological phase I evaluation of Exherin™ (ADH-1), a selective anti-N-cadherin peptide in patients with N-cadherin-expressing solid tumours

BACKGROUND Upregulation of N-cadherin promotes dysregulated cell growth, motility, invasiveness, plus maintenance of vascular stability and is associated with cancer progression in several human tumour types. N-cadherin is expressed also on tumour cells and the anti-N-cadherin cyclic pentapeptide ADH-1, tested in the present study, can exert a direct antitumour effect. PATIENTS AND METHODS Adult patients with advanced solid malignancies expressing N-cadherin on tumour biopsies carried out in the previous 12 months received escalating i.v. doses of ADH-1 given weekly (initially for 3 of 4 weeks, then every week). Plasma pharmacokinetics (PK) was studied at cycle 1. Blood flow changes were assessed after first dosing in all patients treated in the initial regimen. RESULTS In all, 129 patients were screened, 65 (50%) were N-cadherin positive, and 30 were enrolled. The doses ranged from 150 to 2400 mg/m(2); no maximum tolerated dose was reached. Treatment was well tolerated with asthenia as the most frequent adverse event. Two patients with ovarian cancer showed prolonged disease stabilisation while one patient with fallopian tube carcinoma achieved a mixed response. PK was linear in the range of doses tested. CONCLUSION ADH-1 is the first anti-N-cadherin compound tested in humans. In N-cadherin-positive patients, ADH-1 showed an acceptable toxicity profile, linear PK and hints of antitumour activity in gynaecological cancers.

Molecular Alterations and Everolimus Efficacy in Human Epidermal Growth Factor Receptor 2–Overexpressing Metastatic Breast Cancers: Combined Exploratory Biomarker Analysis From BOLERO-1 and BOLERO-3

PURPOSE Two recent phase III trials, BOLERO-1 and BOLERO-3 (Breast Cancer Trials of Oral Everolimus), evaluated the addition of everolimus to trastuzumab and chemotherapy in human epidermal growth factor receptor 2-overexpressing advanced breast cancer. The current analysis aimed to identify biomarkers to predict the clinical efficacy of everolimus treatment. METHODS Archival tumor samples from patients in BOLERO-1 and BOLERO-3 were analyzed using next-generation sequencing, immunohistochemistry, and Sanger sequencing. RESULTS Biomarker data were available for 549 patients. PIK3CA activating mutations and PTEN loss were reported in 30% and 16% of BOLERO-1 samples and in 32% and 12% of BOLERO-3 samples, respectively. PI3K pathway was hyperactive (PIK3CA mutations and/or PTEN loss and/or AKT1 mutation) in 47% of BOLERO-1 and 41% of BOLERO-3 samples. In both studies, differential progression-free survival (PFS) benefits of everolimus were consistently observed in patient subgroups defined by their PI3K pathway status. When analyzing combined data sets of both studies, everolimus was associated with a decreased hazard of progression in patients with PIK3CA mutations (hazard ratio [HR], 0.67; 95% CI, 0.45 to 1.00), PTEN loss (HR, 0.54; 95% CI, 0.31 to 0.96), or hyperactive PI3K pathway (HR, 0.67; 95% CI, 0.48 to 0.93). Patients with wild-type PIK3CA (HR, 1.10; 95% CI, 0.83 to 1.46), normal PTEN (HR, 1.00; 95% CI, 0.80 to 1.26), or normal PI3K pathway activity (HR, 1.19; 95% CI, 0.87 to 1.62) did not derive PFS benefit from everolimus. CONCLUSION This analysis, although exploratory, suggests that patients with human epidermal growth factor receptor 2-positive advanced breast cancer having tumors with PIK3CA mutations, PTEN loss, or hyperactive PI3K pathway could derive PFS benefit from everolimus.

Current and future directions in mammalian target of rapamycin inhibitors development

Introduction: The mammalian target of the rapamycin (mTOR) signalling pathway has a central role in the regulation of cell growth, survival and angiogenesis and the frequent dysregulation of this pathway in tumor cells makes it a crucial target in the treatment of cancer. Temsirolimus and everolimus are approved for use in metastatic renal cell carcinoma and temsirolimus is also approved for mantle cell lymphoma. All three rapalogs, temsirolimus, everolimus and deforolimus, are currently being evaluated in Phase III studies in several tumors. Areas covered: This paper provides a review of the published literature on the mTOR pathway and related pathway signaling, analogs and novel mTOR inhibitors. The most recent and important data on the mTOR pathway, the role of mTOR inhibitors in cancer treatment and the current status of development of second-generation highly potent and selective mTOR inhibitors are overviewed. Expert opinion: The published data on new mTOR inhibitors are still limited, but the available preclinical results indicate that they have a potent antiproliferative activity against a broad panel of tumor cell lines, have a favorable safety profile, can obtain disease stabilization or even tumor regression and, in some cases, enhance the efficacy of other targeted or standard-of-care anticancer drugs when used in vivo in preclinical studies.

Proliferation and estrogen signaling can distinguish patients at risk for early versus late relapse among estrogen receptor positive breast cancers.

IntroductionWe examined if a combination of proliferation markers and estrogen receptor (ER) activity could predict early versus late relapses in ER-positive breast cancer and inform the choice and length of adjuvant endocrine therapy.MethodsBaseline affymetrix gene-expression profiles from ER-positive patients who received no systemic therapy (n = 559), adjuvant tamoxifen for 5 years (cohort-1: n = 683, cohort-2: n = 282) and from 58 patients treated with neoadjuvant letrozole for 3 months (gene-expression available at baseline, 14 and 90 days) were analyzed. A proliferation score based on the expression of mitotic kinases (MKS) and an ER-related score (ERS) adopted from Oncotype DX® were calculated. The same analysis was performed using the Genomic Grade Index as proliferation marker and the luminal gene score from the PAM50 classifier as measure of estrogen-related genes. Median values were used to define low and high marker groups and four combinations were created. Relapses were grouped into time cohorts of 0–2.5, 0–5, 5-10 years.ResultsIn the overall 10 years period, the proportional hazards assumption was violated for several biomarker groups indicating time-dependent effects. In tamoxifen-treated patients Low-MKS/Low-ERS cancers had continuously increasing risk of relapse that was higher after 5 years than Low-MKS/High-ERS cancers [0 to 10 year, HR 3.36; p = 0.013]. High-MKS/High-ERS cancers had low risk of early relapse [0–2.5 years HR 0.13; p = 0.0006], but high risk of late relapse which was higher than in the High-MKS/Low-ERS group [after 5 years HR 3.86; p = 0.007]. The High-MKS/Low-ERS subset had most of the early relapses [0 to 2.5 years, HR 6.53; p < 0.0001] especially in node negative tumors and showed minimal response to neoadjuvant letrozole. These findings were qualitatively confirmed in a smaller independent cohort of tamoxifen-treated patients. Using different biomarkers provided similar results.ConclusionsEarly relapses are highest in highly proliferative/low-ERS cancers, in particular in node negative tumors. Relapses occurring after 5 years of adjuvant tamoxifen are highest among the highly-proliferative/high-ERS tumors although their risk of recurrence is modest in the first 5 years on tamoxifen. These tumors could be the best candidates for extended endocrine therapy.

Multicenter phase I clinical trial of daily and weekly RAD001 (everolimus) in combination with vinorelbine and trastuzumab in patients with HER-2-overexpressing metastatic breast cancer with prior resistance to trastuzumab.

Abstract #406 Background: Resistance to trastuzumab (H) is associated with loss of PTEN and AKT/mTOR activation. Preclinically, RAD001, an oral inhibitor of mTOR, enhances the efficacy of H suggesting that RAD001 could reverse resistance to H.
 Methods: Vinorelbine (V) was administered at a dose of 25 mg/m 2 , IV over 10-15 min on days 1 and 8 q3w. H 4 mg/kg loading dose administered IV over 90 min on Day 1 (if pt was not already receiving H), followed by weekly H 2 mg/kg IV over 30 min. In the daily RAD001 arm, 3 cohorts were planned (2.5, 5 and 10mg) and in the weekly RAD001 arm, 4 cohorts were planned (20, 30, 50 and 70mg). Treatment continued until progression or unacceptable toxicity.
 Results: As of June 10 2008, 28 heavily pretreated pts were enrolled: 15 to 5mg/d, 6 to 20mg/w and 7 to 30mg/w cohorts. All pts received prior taxanes. Median number of prior CT regimens was 3 (range: 1-5). The main safety events were grade 2 and 3 stomatitis which led to dose reduction of RAD001 in 3 pts and dose interruption in 3. Grade 4 and 3 Neutropenia were seen in 24 pts (leading to dose reduction of V in 11 pts). Twenty two pts have been evaluated for efficacy (table 1). 1 pt had a CR (45+ weeks), 2 pts had PR (35+, 38 weeks), 15 pts SD (Median 26+, range 8+ to 58 weeks) and 4 pts PD. Clinical benefit rate (CR+PR+SD > 24 wks) is 55%+.
 Conclusions: Initial findings show that RAD001 is generally well tolerated in combination with V and H and shows promising anticancer activity and clinical benefit in heavily pretreated patients with HER2+ advanced breast cancer. Updated results will be presented.
 Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 406.

Seminars in clinical pharmacology: an introduction to MET inhibitors for the medical oncologist

MET is a tyrosine kinase receptor for hepatocyte growth factor (HGF), primarily expressed on epithelial cells; the activation of MET induces several biological responses relevant for the development and growth of many human cancers. Several human malignancies present altered expression of MET and this is usually associated with poor prognosis and aggressive phenotype. The majority of MET inhibitors in clinical development target directly the receptor through the use of monoclonal antibodies (MAbs) or through small molecule inhibitors of MET kinase activity; small molecule inhibitors are very potent but less specific than MAbs. MET inhibitors are of great clinical interest because of the extensive crosstalk of the HGF/MET axis with many other signaling pathways, including growth factor-dependent pathways (like PI3K/AKT/mTOR,RAS/RAF/ERK) and vascular endothelial growth factor (VEGF) axis. In preclinical studies, the treatment with MET inhibitors could prevent or reverse resistance to inhibitors of growth factor-dependent signaling; this hypothesis is currently tested in phase III trials with anti-epidermal growth factor receptor (EGFR) inhibitors in non-small-cell lung cancer (NSCLC). Based on preclinical and preliminary clinical results, a rational strategy for the clinical development of MET antagonists should include a selection of the tumors with MET overexpression, the identification of prognostic/predictive biomarkers, the evaluation of combinations with anti-VEGF compounds.