Targeting protein kinase C: new therapeutic opportunities against high-grade malignant gliomas?

A large body of evidence suggests that the abnormal phenotype of neoplastic astrocytes, including their excessive proliferation rate and high propensity to invade surrounding tissues, results from mutations in critical genes involved in key cellular events. These genetic alterations can affect cell-surface-associated receptors, elements of signaling pathways, or components of the cell cycle clock, conferring a gain or a loss of relevant metabolic functions of the cells. The understanding of such phenomena may allow the development of more efficacious forms of cancer treatment. Examples are therapies specifically directed against overexpressed epidermal growth factor receptor, hyperactive Ras, excessively stimulated Raf-1, overproduced ornithine decarboxylase, or aberrantly activated cyclin-dependent kinases. The applicability of some of these approaches is now being assessed in patients suffering from primary malignant central nervous system tumors that are not amenable to current therapeutic modalities. Another potentially useful therapeutic strategy against such tumors involves the inhibition of hyperactive or overexpressed protein kinase C (PKC). This strategy is justified by the decrease in cell proliferation and invasion following inhibition of the activity of this enzyme observed in preclinical glioma models. Thus, interference with PKC activity may represent a novel form of experimental cancer treatment that may simultaneously restrain the hyperproliferative state and the invasive capacity of high-grade malignant gliomas without inducing the expected toxicity of classical cytotoxic agents. Of note, the experimental use of PKC-inhibiting agents in patients with refractory high-grade malignant gliomas has indeed led to some clinical responses. The present paper reviews the current status of the biochemistry and molecular biology of PKC, as well as the possibilities for developing novel anti-PKC-based therapies for central nervous system malignancies.     

How do doctors explain randomised clinical trials to their patients?

As part of a larger study designed to improve doctor-patient communication in randomised clinical trials (RCT), we audiotaped the discussions between doctor and patient in which consent was being obtained for a RCT. This paper reports on 82 discussions conducted by 5 clinical oncologists in both District General and University Hospital outpatient departments. When introducing the subject of trials, uncertainty about treatment decisions was expressed by the doctors in the majority of cases (79, 96.3%). This was most often stated in a general sense (78, 95.1%), but some mentioned personal uncertainty (12, 14.6%), an approach which helps to maintain a trusting doctor-patient relationship. The word randomization was mentioned in 51 (62.2%) consultations, although the process itself was usually described implicitly (78, 95.1%), e.g. by telling the patient that they would be allocated either one or other treatment. Analogies were used in 28 (34.1%) cases to describe the randomisation process. In addition, although treatments and side-effects were described frequently, (68, 82.9%) and (72, 87.8%) respectively, information leaflets about the trials were not given to 23 (28%) patients. The study shows that U.K. clinicians adopt individual methods when providing information and eliciting consent to trials.     

Phase 0 clinical trials in oncology: a paradigm shift for early drug development?

Purpose  To review the potential impact of Phase 0 trials conducted under the United States Food and Drug Administration (FDA) exploratory IND guidance on oncology drug development. Methods  The FDA’s exploratory IND guidance document is examined in detail and its practical application to specific first-in-human proof of concept clinical studies called Phase 0 trials is discussed. Results  Phase 0 trials represent a novel strategy for accelerating the development of the next generation of anticancer treatments. Phase 0 studies are conducted prior to conventional toxicity-defined dose-escalation studies and these trials do not explore maximum toxicity levels and by definition are devoid of any therapeutic or diagnostic intent. They require less extensive formulation and non-clinical toxicity testing than conventional first-in-human Phase I trials. This pathway may be valuable in reducing the time and resources required to initiate clinical testing and it may also be useful in guiding the later stages of drug development. Alternatively, the early termination of a less than promising lead compounds could help in selecting the best agents for later clinical development. Possible disadvantages include the ethical challenge of testing non-therapeutic drug regimens in cancer patients and the need to conduct standard dose-escalation Phase I studies later in development. Conclusions  The potential of this novel pathway to accelerate drug development makes it worthy of further exploration, and National Cancer Institute has recently completed a Phase 0 trial demonstrating its applicability to targeted anticancer agents.     

The neutrophil–lymphocyte ratio and its utilisation for the management of cancer patients in early clinical trials

Background:

Inflammation is critical to the pathogenesis and progression of cancer, with a high neutrophil–lymphocyte ratio (NLR) associated with poor prognosis. The utility of studying NLR in early clinical trials is unknown.

Methods:

This retrospective study evaluated 1300 patients treated in phase 1 clinical trials between July 2004 and February 2014 at the Royal Marsden Hospital (RMH), UK. Data were collected on patient characteristics and baseline laboratory parameters.

Results:

The test cohort recruited 300 patients; 53% were female, 35% ECOG 0 and 64% ECOG 1. RMH score was 0–1 in 66% and 2–3 in 34%. The median NLR was 3.08 (IQR 2.06–4.49). Median OS for the NLR quartiles was 10.5 months for quartile-1, 10.3 months for quartile-2, 7.9 months for quartile-3 and 6.5 months for quartile-4 (P<0.0001). Univariate analysis identified RMH score (HR=0.55, P<0.0001), ECOG (HR=0.62, P=0.002) and neutrophils (HR=0.65, P=0.003) to be associated with OS. In multivariate analysis, adjusting for RMH score, ECOG, neutrophils and tumour type, NLR remained significantly associated with OS (P=0.002), with no association with therapeutic steroid use. These results were validated in a further 1000 cancer patients. In the validation cohort, NLR was able to discriminate for OS (P=0.004), as was the RMH score. This was further improved on in the RMH score+NLR50 and RMH score+Log₁₀NLR models, with an optimal NLR cutoff of 3.0.

Conclusions:

NLR is a validated independent prognostic factor for OS in patients treated in phase 1 trials. Combining the NLR with the RMH score improves the discriminating ability for OS.     

On-going clinical trials for elderly patients with a hematological malignancy: are we addressing the right end points?

BackgroundCancer societies and research cooperative groups worldwide have urged for the development of cancer trials that will address those outcome measures that are most relevant to older patients. We set out to determine the characteristics and study objectives of current clinical trials in hematological patients.MethodThe United States National Institutes of Health clinical trial registry was searched on 1 July 2013, for currently recruiting phase I, II or III clinical trials in hematological malignancies. Trial characteristics and study objectives were extracted from the registry website.ResultsIn the 1207 clinical trials included in this overview, patient-centered outcome measures such as quality of life, health care utilization and functional capacity were only incorporated in a small number of trials (8%, 4% and 0.7% of trials, respectively). Even in trials developed exclusively for older patients, the primary focus lies on standard end points such as toxicity, efficacy and survival, while patient-centered outcome measures are included in less than one-fifth of studies.ConclusionCurrently on-going clinical trials in hematological malignancies are unlikely to significantly improve our knowledge of the optimal treatment of older patients as those outcome measures that are of primary importance to this patient population are still included in only a minority of studies. As a scientific community, we cannot continue to simply acknowledge this issue, but must all participate in taking the necessary steps to enable the delivery of evidence-based, tailor-made and patient-focused cancer care to our rapidly growing elderly patient population.     

The EORTC early clinical trials cooperative group experience with 5-aza-2′-deoxycytidine (NSC 127716) in patients with colo-rectal,head and neck,renal carcinomas and malignant melanomas

The Early Clinical Trials Cooperative Group of the EORTC conducted several phase II studies with a pyrimidine analogue of deoxycytidine, 5-aza-2′-deoxycytidine (DAC). The drug was given as three consecutive 1 h i.v. infusions of 75 mg/m², separated by intervals of 7 h; courses were repeated every 5 weeks. A total of 101 eligible patients were studied: 42 with colo-rectal adenocarcinoma, 27 with squamous cell carcinoma of the head and neck, 18 with malignant melanoma and 14 with renal cell carcinoma. Drug-induced toxicities consisted of moderate myelosuppression, and nausea and vomiting. One single partial remission was seen in a patient with malignant melanoma. DAC given in this dose and schedule is devoid of antitumour activity in adult patients with these refractory types of carcinomas.     

Is B-Raf a good therapeutic target for melanoma and other malignancies?

The RAF family members, A-Raf, B-Raf, and C-Raf (or Raf-1), are intermediate molecules in the mitogen-activated protein (MAP) kinase [Ras/Raf/MAP kinase/extracellular signal-regulated kinase (Erk) kinase (MEK)/Erk] pathway, which relays extracellular signals from the cell membrane to the nucleus via a cascade of phosphorylation events ultimately promoting cancer development. This pathway is activated by mutation in approximately 7% of all human cancers. B-Raf is one of the proteins frequently mutated to an active form during tumor development. Therefore, B-Raf is an attractive cancer target but lack of clinical efficacy using agents targeting this protein has raised serious doubts about its therapeutic utility. Design of more effective B-Raf inhibitory agents, targeting other members of the signaling cascade for greater clinical efficacy or inhibiting B-Raf in combination with other targets, is being evaluated to resolve these perplexing issues. Here, we discuss recent progress, using preclinical models and clinical studies, to resolve the controversy of whether B-Raf would be a good therapeutic target for melanoma and other malignancies.     

Why is autophagy important for melanoma? Molecular mechanisms and therapeutic implications

As the principle lysosomal mediated mechanism for the degradation of aged or damaged organelles and proteins, autophagy (self-eating) is generally considered a pro-survival process activated by cells to sustain life in presence of adverse environmental conditions such as nutrient shortage and/or in presence of cytotoxic compounds [1]. Upon activation, cytoplasmic material is sequestered into double-membrane vesicles (autophagosomes) then targeted for degradation by fusion with lysosomes (autolysosomes); metabolic activity and cell survival are consequently sustained by recycling the degradation products. Basal autophagy occurs in almost all cell types, though at different degree, as a finely regulated “quality control” process to prevent cell damage, for the demolition of cellular structures during cell/tissue remodelling, and to ensure the maintenance of cellular homeostasis through recycling cellular components/molecules [2], [3].Autophagy is stimulated in response to both physiological and pathological conditions such as starvation, hypoxia and low energy, pathogen infection and protein aggregates.Although it's clear that autophagy is also involved in cancer, its role, however, is complex since it can both suppress and promote tumorigenesis [4]. Consequently, it is generally accepted that while autophagy is used by advanced stage cancers to maintain tumour survival, loss of autophagy in earlier stages is associated with tumour development.Accordingly, it is now apparent that aberrant control of autophagy is among key hallmarks of cancer, with several studies now demonstrating this process is deregulated also in melanoma [5], [6].     

Eligibility of patients with renal impairment for Phase I trials: Time for a rethink?

Since the inception of Phase I clinical trials in cancer, patients with renal dysfunction have commonly been excluded from participation because of a poor outlook. Most cancer drugs are approved with limited information on the pharmacokinetics and/or pharmacodynamics of the drugs in patients with renal dysfunction, and no formal renal dysfunction study is ever undertaken. Patients with asymptomatic mild to moderate renal dysfunction pose an increasingly frequent challenge for clinicians. In this paper, we discuss that a subset of patients with asymptomatic mild to moderate renal impairment might be appropriately entered into selected Phase I trials. This will provide physicians timely data of the new agents in this patient population and increase patients’ access to experimental treatments.     

Phase II clinical trials of cisplatin-then-paclitaxel and paclitaxel-then-cisplatin in patients with previously untreated?advanced?epithelial ovarian?cancer

Purpose:To examine the activity and safety of two sequentiallyscheduled chemotherapy regimens comprising four cycles of paclitaxel (pctx)200 mg/m²/3 hours then four cycles of cisplatin (cisDDP) 100mg/m², and vice versa, in patients with previouslyuntreated advanced ovarian cancer. Patients and methods:Between January 1994 and February 1996, werecruited 30 patients to the pctx-then-cisDDP regimen and 29 tocisDDP-then-pctx, in parallel phase II trials. Results:Both regimens were predictably active with responses seenin 22 of 30 patients (OR 74%; CR 27%, PR 47%) treatedwith pctx-then-cisDDP, as against 13 of 21 patients (OR 62%; CR38%, PR 24%) treated with cisDDP-then-pctx. The OR rate to fourcycles of pctx (induction) was 43%, with 27% diseaseprogression; the OR to four cycles of cisDDP (induction) was 57%, with5% progression. However, progression rates across both induction andconsolidation phases were 16% (pctx-then-cisDDP) and 29%(cisDDP-then-pctx). Both regimens were unacceptably neurotoxic, 11 patientssuffering grade 3 sensory neurotoxicity (5 on pctx-then-cisDDP, 6 oncisDDP-then-pctx) and 20 having grade 3 deafness (9 on pctx-then-cisDDP, 11on cisDDP-then-pctx). Conclusion:The activity of these sequential regimens justifiestheir further development using the less neurotoxic platinum analoguecarboplatin, perhaps combining paclitaxel with other platinum non-crossresistant drugs.     

Angiogenesis,vasculogenic mimicry and vascular invasion in cutaneous malignant melanoma – implications for therapeutic strategies and targeted therapies

Angiogenesis, defined as new vessel growth from a pre-existing vessel, has been shown to be crucial for tumor survival and growth in several lineage-unrelated malignancies including melanoma. The concept of vasculogenic mimicry, a highly patterned microcirculation independent of angiogenesis, has also been described in melanoma. The prognostic value of vascular invasion, characterized by the presence of tumor cells within vascular channels, in melanoma remains controversial as in the current American Joint Committee on Cancer-staging system for melanoma vascular invasion is not included for microscopic staging purposes. This review summarizes contemporary understanding of these three processes i.e. angiogenesis, vasculogenic mimicry, and vascular invasion in an effort to uncover putative targets as therapeutic strategies in melanoma.