One of the abiding mysteries of all multi-cellular organisms is the requirement for controlled death —apoptosis — of unwanted cells. It has been estimated that without apoptosis an 80 year old person would have two tons of bone marrow and lymph nodes and an intestine 16 kilometers long.1 Progress in defining pathways of apoptosis has revealed complex interconnections between various cell death programs that may affect the treatment of a wide range of diseases.2–10 This article reviews advances in our understanding of mechanisms of cell death and highlights current and potential therapies based upon these concepts.

Perhaps the most widely used classification of mammalian cell death consists of two types: apoptosis and necrosis.3,4,11 Autophagy, which has recently been proposed as a third distinct mode of cell death, is a process by which cells generate energy and metabolites by digesting organelles or macromolecules.12–15. Normally, autophagy allows a starving cell, or a cell deprived of growth factors to survive.12–15 Ultimately, however, cells deprived of nutrients for extended periods will digest all available substrates and die an ‘autophagy-associated cell death’. Distinctions between apoptosis, necrosis, and autophagy entail differences in mode-specific or selective morphologic, biochemical, and molecular attributes (Fig. 1).3,4,11



Figure 1

Schematic diagram showing 3 possible pathways of cell death



An important concept embodied in part by these attributes is “programmed” cell death. Cell death is “programmed” if it is genetically controlled. The two fundamental types of programmed cell death are apoptosis and autophagy-associated cell death.3,12 The recognition that cell death can occur by genetically controlled processes has enabled advances in unraveling the mechanisms of many diseases. As a result, we now have improved knowledge of the initiation of cell death programs and the relevant signaling pathways. This information has facilitated development of pharmacologic agents that initiate or inhibit programmed cell death.6–8,16 Moreover, there is now evidence that necrosis, traditionally considered an accidental form of cell death, can, in certain instances, be initiated or modulated under programmed control mechanisms.17–21

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MECHANISMS OF DISEASE Cell Death

For over three decades, a mainstay and goal of clinical oncology has been the development of therapies promoting the effective elimination of cancer cells by apoptosis. This programmed cell death process is mediated by several signalling pathways (referred to as intrinsic and extrinsic) triggered by multiple factors, including cellular stress, DNA damage and immune surveillance. The interaction of apoptosis pathways with other signalling mechanisms can also affect cell death. The clinical translation of effective pro-apoptotic agents involves drug discovery studies (addressing the bioavailability, stability, tumour penetration, toxicity profile in non-malignant tissues, drug interactions and off-target effects) as well as an understanding of tumour biology (including heterogeneity and evolution of resistant clones). While tumour cell death can result in response to therapy, the selection, growth and dissemination of resistant cells can ultimately be fatal. In this Review, we present the main apoptosis pathways and other signalling pathways that interact with them, and discuss actionable molecular targets, therapeutic agents in clinical translation and known mechanisms of resistance to these agents.

Targeting apoptosis in cancer therapy

Triggering of tumour cell apoptosis is the foundation of many cancer therapies. Death receptors of the tumour necrosis factor (TNF) superfamily have been largely characterized, as have the signals that are generated when these receptors are activated. TNF-related apoptosis-inducing ligand (TRAIL) receptors (TRAILR1 and TRAILR2) are promising targets for cancer therapy. Herein we review what is known about the molecular control of TRAIL-mediated apoptosis, the role of TRAIL in carcinogenesis and the potential therapeutic utility of recombinant TRAIL and agonistic antibodies against TRAILR1 and TRAILR2.

http://dipbsf.uninsubria.it/monti/BFPN%202009/TRAIL-2008.pdf?origin=publication_detail

The TRAIL apoptotic pathway in cancer onset, progression and therapy

Each day, the human body eliminates billions of unwanted cells by apoptotic suicide. Apoptosis provides an important barrier against cancer; however, specific mutations enable some tumour cells to escape apoptotic death and become more malignant. Two signalling pathways initiate apoptosis: one acts through intracellular Bcl-2 proteins, the other through cell-surface pro-apoptotic receptors. New molecular insights have inspired the development of pro-apoptotic receptor agonists (PARAs), including the recombinant human protein apoptosis ligand 2/TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) and agonistic monoclonal antibodies to its signalling receptors. Acting alone, or in concert with other agents, PARAs may overcome key apoptosis blocks and direct cancer cells to self-destruct.

http://dipbsf.uninsubria.it/monti/BFPN%202009/trail2008.pdf

Directing cancer cells to self-destruct with pro-apoptotic receptor agonists.

Unlike other members of the TNF superfamily, the TNF-related apoptosis-inducing ligand (TRAIL, also known as Apo2L) possesses the unique capacity to induce apoptosis selectively in cancer cells in vitro and in vivo. This exciting discovery provided the basis for the development of TRAIL-receptor agonists (TRAs), which have demonstrated robust anticancer activity in a number of preclinical studies. Subsequently initiated clinical trials testing TRAs demonstrated, on the one hand, broad tolerability but revealed, on the other, that therapeutic benefit was rather limited. Several factors that are likely to account for TRAs' sobering clinical performance have since been identified. First, because of initial concerns over potential hepatotoxicity, TRAs with relatively weak agonistic activity were selected to enter clinical trials. Second, although TRAIL can induce apoptosis in several cancer cell lines, it has now emerged that many others, and importantly, most primary cancer cells are resistant to TRAIL monotherapy. Third, so far patients enrolled in TRA-employing clinical trials were not selected for likelihood of benefitting from a TRA-comprising therapy on the basis of a valid(ated) biomarker. This review summarizes and discusses the results achieved so far in TRA-employing clinical trials in the light of these three shortcomings. By integrating recent insight on apoptotic and non-apoptotic TRAIL signaling in cancer cells, we propose approaches to introduce novel, revised TRAIL-based therapeutic concepts into the cancer clinic. These include (i) the use of recently developed highly active TRAs, (ii) the addition of efficient, but cancer-cell-selective TRAIL-sensitizing agents to overcome TRAIL resistance and (iii) employing proteomic profiling to uncover resistance mechanisms. We envisage that this shall enable the design of effective TRA-comprising therapeutic concepts for individual cancer patients in the future.

/pdf/getting-trail-back-on-track-for-cancer-therapy-2xgo2qs2df.pdf

Getting TRAIL back on track for cancer therapy

Purpose: To assess the safety and tolerability, pharmacokinetics, and early evidence of antitumor activity of escalating doses of lexatumumab (HGS-ETR2), a fully human agonistic monoclonal antibody which targets and activates the tumor necrosis factor–related apoptosis-inducing ligand receptor 2 (TRAIL-R2) in patients with advanced solid malignancies. Experimental Design: In this phase 1, open label study, patients with advanced solid malignancies were treated with escalating doses of lexatumumab administered i.v. over 30 to 120 min every 21 days. A cohort of four patients, which could be expanded to six patients, was studied at each dose level. The dose-limiting toxicity (DLT) dose was defined as the dose at which the incidence of DLT in the first two cycles was ≥33%. The maximum tolerated dose was defined as the highest dose at which Results: Thirty-seven patients received 120 cycles of lexatumumab at doses ranging from 0.1 to 20 mg/kg every 21 days as of May 2006. The 20 mg/kg dose was identified as the DLT dose based on DLTs in three of seven patients treated with this dose; DLTs included asymptomatic elevations of serum amylase, transaminases, and bilirubin. The 10 mg/kg dose cohort was expanded to 12 patients and the 10 mg/kg dose was identified as the maximum tolerated dose. The mean (±SD) clearance and apparent terminal half-life values at the 10 mg/kg dose averaged 6.0 (2.9) mL/d/kg and 16.4 (10.9) days, respectively. Twelve patients had durable stable disease that lasted a median of 4.5 months, including three patients with sarcoma having prolonged stable disease (≥6.7 months). Immunohistochemistry for TRAIL-R2 showed specific staining in >10% of tumor cells for 16 of the 20 evaluable specimens submitted (80%). Conclusions: Lexatumumab was safe and well tolerated at doses up to and including 10 mg/kg every 21 days. Lexatumumab was associated with sustained stable disease in several patients. Pharmacokinetics were linear over the dose range studied, and consistent with a two-compartment model with first-order elimination from the central compartment. Additional evaluation of this novel apoptosis-inducing agent, particularly in combination with chemotherapy agents, is warranted and ongoing.

https://clincancerres.aacrjournals.org/content/clincanres/13/20/6187.full.pdf

Phase 1 and pharmacokinetic study of lexatumumab in patients with advanced cancers.

BACKGROUND Malignant germ cell tumour of the ovary occurs in up to 0.07% of woman globally. Due to its rarity, evidence for treatment is lacking and often extrapolates clinical trial results of testicular germ cell cancers. The investigation on this rare tumour is further compounded by the fact that its occurrence in the adult population is even less compared to their paediatric counterpart. At present, the effectiveness of chemotherapy, regardless of stage in malignant germ cell tumour of the ovary is not entirely clear. OBJECTIVES To evaluate the effectiveness and safety of chemotherapy in adult women with early stage, advanced and recurrent malignant germ cell ovarian cancers. SEARCH STRATEGY We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Issue 1, 2010, Cochrane Gynaecological Cancer Group Trials Register, MEDLINE and EMBASE up to April 2010. We also searched registers of clinical trials, abstracts of scientific meetings and reference lists of included studies. SELECTION CRITERIA We searched for randomised controlled trials (RCTs), quasi-RCTs and non-randomised studies that compared systemic therapy in adult women diagnosed with germ cell ovarian cancer who have confirmed pathological diagnoses. DATA COLLECTION AND ANALYSIS Two review authors independently assessed whether potentially relevant studies met the inclusion criteria, abstracted data and assessed risk of bias. MAIN RESULTS We found one RCT and one retrospective study that met our inclusion criteria. The data from these studies were too sparse to adequately assess the effectiveness and safety of adjuvant chemotherapy in the treatment of malignant germ cell ovarian cancer. All comparisons were restricted to single study analyses and this review was only based on 32 women, so it was not adequately powered to detect differences in survival. Adverse effects of treatment and recurrence-free survival were incompletely documented and QoL was not reported in any of the studies. We did not find any studies that reported specifically on adults so there were problems in separating data on adults and children in many of the potentially relevant studies. AUTHORS' CONCLUSIONS We found only low quality evidence on the use of chemotherapy in malignant germ cell tumours of the ovaries. Therefore we are unable to reach definite conclusions about the relative benefits and harms of chemotherapy use in this disease regardless of disease stage. Due to the benefit of chemotherapy in germ cell cancer of the testis, a trial of chemotherapy versus best supportive care is unlikely to be feasible. Despite this, good quality randomised studies are warranted in this disease to define the role of chemotherapy (type of chemotherapy, duration of treatment, benefit, short and long term toxicities). Given the rarity of this disease, we feel a trans-global approach would be essential in order to perform such trials.

/pdf/chemotherapy-for-malignant-germ-cell-ovarian-cancer-in-adult-f9oqcynri1.pdf

L. Li

Papers

Phase 1 and pharmacokinetic study of lexatumumab in patients with advanced cancers.

Chemotherapy for malignant germ cell ovarian cancer in adult patients with early stage, advanced and recurrent disease

573 POSTER Phase I study of BIBW2992, an oral irreversible dual EGFR/HER2 inhibitor, showing activity in tumors with mutated EGFR

Carboplatin and pemetrexed in the management of malignant pleural mesothelioma: a realistic treatment option?