The formulation in 1874 of the biogenetic law by Ernst Haeckel as "ontogeny recapitulates phylogeny" emphasized the structural similarities detected in metazoans between their developmental and ancestral forms. More recently, many workers have independently commented on the similarities observed between the behaviours displayed by dedifferentiated cancer cells and their embryonic precursors. This review will explore a possible linkage between these disparate observations and will suggest that cancer cells behave in ways that are reminiscent of primitive eukaryotic cells. In particular, we suggest that the acquisition of a multicellular level of organization during early metazoan evolution required a critical and difficult change in growth strategy as germ line and somatic cells became distinct. Whereas unicellular free living eukaryotes follow a simple strategy of rapid division as long as conditions permit, the elaboration of powerful growth inhibitory pathways must have been necessary in primitive multicellular organisms to enable some but not all sister cells to stop dividing, even under conditions of nutrient abundance. This limitation on cellular growth would than have permitted the appearance of tissues and organs with differentiated characteristics, ultimately enabling the enhanced survival of the meiotic lineage. Cancer cells might therefore be considered to represent, with their loss of tumor suppressor inhibitory activity and elevation of oncogene stimulatory activity, a reversion to a more primitive evolutionary state capable of indeterminate growth at the expense of the host. By this analogy, the growth phenotypes displayed by cancer cells, embryonic cells, and free-living eukaryotes are fundamentally similar.
Background: Efatutazone, a highly-selective peroxisome proliferator-activated receptor gamma (PPARδ) agonist, has demonstrated antitumor activity in multiple preclinical cancer models, including NSCLC, and has shown anticancer effects and a favorable toxicity profile in Phase 1 trials. The current study evaluated the safety and efficacy of efatutazone in combination with carboplatin and paclitaxel as first-line therapy for NSCLC. Methods: Patients with histologically/cytologically confirmed, untreated metastatic NSCLC, with no significant pleural effusion or pleural involvement from the tumor and an ECOG score of 0-1 participated in this 2-part, multinational study. Part 1 comprised a single-arm portion evaluating safety; Part 2, a double-blind, placebo-controlled, randomized Phase 2 portion evaluating safety and efficacy. Efatutazone (0.5 mg) or placebo was administered orally BID, continuously. Carboplatin was administered at a projected AUC of 6 mg/ml*min and paclitaxel at 200 mg/m2. In Part 1, patients were evaluated for treatment-related dose-limiting toxicities (DLTs). In Part 2, the primary endpoint was the progression-free survival (PFS) rate at Week 18, assessed by the investigators using RECIST. Results: 3 patients enrolled in Part 1; no DLTs were observed. 108 patients were randomized into Part 2. Demographic characteristics were generally similar between treatment arms with fewer patients in the efatutazone arm aged > 65 years (11% vs 28%), female (24% vs 32%), ECOG = 0 (30% vs 35%), and with squamous histology (26% vs 37%). Efatutazone was associated with a lower PFS rate at Week 18 vs placebo (41.1% [95% CI: 26.3, 55.3%] vs 64.9% [95% CI: 50.1, 76.3%]; P < 0.001) and a shorter PFS (102 vs 142 days; HR = 1.62, P = 0.04). There was no difference in overall survival (HR = 1.11, P = 0.71) at a median duration of follow-up of 6.7 months. Most adverse events more frequent with efatutazone were consistent with fluid retention, a known side effect of PPARδ agonists, and included edema, weight gain, pleural effusion, dyspnea, and anemia. In addition, a higher incidence of febrile neutropenia, nausea, and pain in extremity occurred in the efatutazone arm. Exploratory analyses are ongoing to try to understand the reason for the unexpected negative effect on PFS. The higher incidence of pleural effusion with efatutazone, which might be related to a treatment side effect rather than tumor progression, may provide some explanation: in some cases, pleural effusion was judged as progressive disease, whereas other target lesions were stable; no cytology was obtained in these cases. Interpretation: The efatutazone safety profile in this trial was largely consistent with prior studies and known effects of PPARδ agonists. Efatutazone does not improve the efficacy of carboplatin/paclitaxel as first-line therapy of unselected patients with NSCLC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4606. doi:1538-7445.AM2012-4606
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