Jennifer Brown

Transcription Factor NF-κB Differentially Regulates Death Receptor 5 Expression Involving Histone Deacetylase 1

ABSTRACT The transcription factor nuclear factor κB (NF-κB) regulates the expression of both antiapoptotic and proapoptotic genes. Death receptor 5 (DR5, TRAIL-R2) is a proapoptotic protein considered to be a potential target for cancer therapy, and its expression is mediated by NF-κB. The mechanism of NF-κB-induced DR5 expression is, however, unknown. Herein, we determined that etoposide-induced DR5 expression requires the first intronic region of the DR5 gene. Mutation of a putative NF-κB binding site in this intron eliminates DR5 promoter activity, as do mutations in the p53 binding site in this region. Reduction in p53 expression also blocks p65 binding to the intronic region of the DR5 gene, indicating cooperation between p53 and p65 in DR5 expression. In contrast, the antiapoptotic stimulus, epidermal growth factor (EGF), fails to increase DR5 expression but effectively activates NF-κB and induces p65 binding to the DR5 gene. EGF, however, induces the association of histone deacetylase 1 (HDAC1) with the DR5 gene, whereas etoposide treatment fails to induce this association. Indeed, HDAC inhibitors activate NF-κB and p53 and upregulate DR5 expression. Blockage of DR5 activation decreased HDAC inhibitor-induced apoptosis, and a combination of HDAC inhibitors and TRAIL increased apoptosis. This provides a mechanism for regulating NF-κB-mediated DR5 expression and could explain the differential roles NF-κB plays in regulating apoptosis.

A phase I, pharmacokinetic and pharmacodynamic study of GSK2256098, a focal adhesion kinase inhibitor, in patients with advanced solid tumors.

BACKGROUNDnFocal adhesion kinase (FAK) is important in cancer growth, survival, invasion, and migration. The purpose of this study was to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the FAK inhibitor, GSK2256098, in cancer patients.nnnPATIENTS AND METHODSnThe dose of GSK2256098 was escalated, in cohorts of patients with advanced cancer, from 80 to 1500 mg, oral twice daily (BID), until the MTD was determined. Serial blood samples were obtained from all patients, and the PK was determined. Paired tumor biopsies were obtained in select patients, and the level of phospho-FAK (pFAK) was determined.nnnRESULTSnSixty-two patients (39 males, 23 females; median age 61 y.o., range 21-84) received GSK2256098. Dose-limiting toxicities of grade 2 proteinuria (1000 mg BID), grade 2 fatigue, nausea, vomiting (1250 mg BID), and grade 3 asthenia and grade 2 fatigue (1500 mg BID) were reported with the MTD identified as 1000 mg BID. The most frequent adverse events (AEs) were nausea (76%), diarrhea (65%), vomiting (58%), and decreased appetite (47%) with the majority of AEs being grades 1-2. The PK was generally dose proportional with a geometric mean elimination half-life range of 4-9 h. At the 750, 1000, and 1500 mg BID dose levels evaluated, the pFAK, Y397 autophosphorylation site, was reduced by ∼80% from baseline. Minor responses were observed in a patient with melanoma (-26%) and three patients with mesothelioma (-13%, -15%, and -17%). In the 29 patients with recurrent mesothelioma, the median progression-free survival was 12 weeks with 95% CI 9.1, 23.4 weeks (23.4 weeks merlin negative, n = 14; 11.4 weeks merlin positive, n = 9; 10.9 weeks merlin status unknown, n = 6).nnnCONCLUSIONSnGSK2256098 has an acceptable safety profile, has evidence of target engagement at doses at or below the MTD, and has clinical activity in patients with mesothelioma, particularly those with merlin loss.

Phase Ib/II study of elisidepsin in metastatic or advanced gastroesophageal cancer (IMAGE trial)

PurposeTo determine the recommended dose and antitumor activity of single-agent elisidepsin as a 24-h intravenous (i.v.) infusion fortnightly [biweekly, d1 and 15 every 4xa0weeks (q4wk); Arm A, dose-intensity strategy] or as a 3-h i.v. infusion weekly (d1, 8, 15 and 22 q4wk; Arm B, dose-density strategy) in adult patients with unresectable, locally advanced or metastatic pretreated esophageal, gastroesophageal junction and gastric cancer.MethodsPatients were randomized to one of two elisidepsin dosing schedules. Phase Ib starting doses were 8.0xa0mg flat dose (FD) in Arm A and 3.0xa0mg FD in Arm B. Phase II subsequently explored antitumor activity of both dosing schedules at the respective recommended doses.ResultsForty-four patients received elisidepsin: 12 in stage Ib and 32 in stage II. The recommended doses were defined as 10xa0mg FD (Arm A) and 3.75xa0mg FD (Arm B). Both schedules were well tolerated. Most adverse events were mild or moderate, reversible and predictable with no meaningful differences between schedules. The pharmacokinetic profiles of both schedules were similar to those reported previously in patients with solid tumors treated with a comparable dose. An interim analysis found tumor control in one patient receiving elisidepsin fortnightly, and in none given elisidepsin weekly; patient accrual was therefore discontinued due to lack of efficacy.ConclusionsBoth schedules at the recommended doses presented an acceptable safety profile, but lack of response means that we do not recommend further evaluation of single-agent elisidepsin as chemotherapy for unresectable, locally advanced or metastatic gastroesophageal cancer.

Circulating biomarkers in cancer care: What possible use?

The practice of the physician has changed greatly in the last 100 years. Yet, the fundamental role remains constant: it is the physicians function to make a diagnosis, assess prognosis, choose and deliver the most effective treatment and then to assess the adequacy of that treatment (both in terms of effectiveness and safety). Whereas our predecessors were almost entirely reliant on clinical history and examination findings in conducting these assessments, the 21st century physician is aided by a plethora of blood tests, imaging investigations, electrophysiological recordings and morphological and molecular analyses of tissue samples. For many patients, the totality of these newer tests contributes relatively little to their journey, whilst, for some, key tests can dictate the direction of travel and, sometimes, the ultimate destination.

Pharmacokinetics of carfilzomib in patients with advanced malignancies and varying degrees of hepatic impairment: an open-label, single-arm, phase 1 study

AbstractBackgroundCarfilzomib is approved in the United States and Europe for treatment of relapsed or refractory multiple myeloma (MM). This study evaluated pharmacokinetics (PK) and safety of carfilzomib in patients with relapsed or progressive advanced malignancies and varying degrees of impaired hepatic function.MethodsPatients with normal hepatic function (normal) or hepatic impairment (mild, moderate, or severe) received carfilzomib infusion in 28-day cycles. The primary objective was to assess the influence of hepatic impairment on carfilzomib PK following 27 and 56xa0mg/m2 doses.ResultsThe majority of patients enrolled in this study had solid tumors (nxa0=xa044) vs. MM (nxa0=xa02) since patients with multiple myeloma do not tend to have severe hepatic impairment in the same way as patients with solid tumors. A total of 11 normal and 17 mild, 14 moderate, and 4 severe hepatic impairment patients were enrolled. Compared with patients with normal hepatic function, patients with mild and moderate hepatic impairment had 44 and 26% higher carfilzomib AUC0–last, respectively (27xa0mg/m2 dose); increases at the 56xa0mg/m2 dose were 45 and 21%, respectively. Considerable PK variability (% coefficient of variation in AUC ≤100%) was discerned and no consistent trend of increasing exposure resulting from increasing hepatic impairment severity (moderate vs. mild) was seen. The observed adverse event (AE) profile in patients of mostly solid tumors was consistent with the known safety profile of carfilzomib, with the exception of an increased frequency of AEs consistent with hepatic function abnormalities.ConclusionsIn this population of primarily advanced solid tumor patients, patients with mild and moderate hepatic impairment had approximately 20–50% higher carfilzomib AUC vs. normal hepatic function patients. These increases are unlikely to be clinically significant, in light of the intrinsic PK variability and exposure–response relationship of carfilzomib.n Trial registrationhttp://clinicaltrials.gov NCT01949545; date of registration: September 6, 2013

Metastatic Pancreatic Cancer: Systemic Therapy

Infiltrating ductal adenocarcinoma of the pancreas has an aggressive nature. Approximately 90% of patients have surgically unresectable disease at the time of diagnosis. In addition, the majority of the selected patients who undergo potentially curative resection for small, localised lesions inevitably develop recurrent or metastatic disease. Most systemic therapies have limited efficacy in patients with metastatic disease. Gemcitabine, with or without erlotinib, has modest clinical benefit and a marginal survival advantage in patients with metastatic pancreatic cancer and has become a standard of care for these patients. However, the median survival of patients with metastatic pancreatic cancer remains poor and is less than 6 months. This chapter gives an overview of the various monotherapy and combination chemotherapy regimens that have been evaluated in this disease, discusses the studies which have incorporated molecularly targeted agents into the treatment regimens, and highlights the challenges in developing therapeutic strategies to improve survival in metastatic pancreatic cancer.