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Alterations in fibroblast growth factor receptor (FGFR) genes have been identified as potential driver oncogenes. Pharmacological targeting of FGFRs may therefore provide therapeutic benefit to selected cancer patients, and proof-of-concept has been established in early clinical trials of FGFR inhibitors. Here, we present the molecular structure and preclinical characterization of INCB054828 (pemigatinib), a novel, selective inhibitor of FGFR 1, 2, and 3, currently in phase 2 clinical trials. INCB054828 pharmacokinetics and pharmacodynamics were investigated using cell lines and tumor models, and the antitumor effect of oral INCB054828 was investigated using xenograft tumor models with genetic alterations in FGFR1, 2, or 3. Enzymatic assays with recombinant human FGFR kinases showed potent inhibition of FGFR1, 2, and 3 by INCB054828 (half maximal inhibitory concentration [IC50] 0.4, 0.5, and 1.0 nM, respectively) with weaker activity against FGFR4 (IC50 30 nM). INCB054828 selectively inhibited growth of tumor cell lines with activation of FGFR signaling compared with cell lines lacking FGFR aberrations. The preclinical pharmacokinetic profile suggests target inhibition is achievable by INCB054828 in vivo with low oral doses. INCB054828 suppressed the growth of xenografted tumor models with FGFR1, 2, or 3 alterations as monotherapy, and the combination of INCB054828 with cisplatin provided significant benefit over either single agent, with an acceptable tolerability. The preclinical data presented for INCB054828, together with preliminary clinical observations, support continued investigation in patients with FGFR alterations, such as fusions and activating mutations., Competing Interests: Holly Koblish, Liangxing Wu, Kevin Bowman, Sharon Diamond, Darlise DiMatteo, Yue Zhang, Michael Hansbury, Mark Rupar, Xiaoming Wen, Paul Collier, Patricia Feldman, Ronald Klabe, Krista A. Burke, Maxim Soloviev, Christine Gardiner, Xin He, Alla Volgina, Maryanne Covington, Richard Wynn, Timothy C. Burn, Swamy Yeleswaram, Wenqing Yao are employees of Incyte Corporationand own Incyte stock. Phillip C. C. Liu, Bruce Ruggeri, Peggy Scherle, Reid Huber, and Gregory Hollis were employees of Incyte employees Corporation at the time of this work and own Incyte stock.Our commercial affiliation does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Fatigue is one of the most distressing symptoms of cancer patients. Its characteristics and impact on quality of life have not been fully explored and treatment of cancer-related fatigue in Italian oncological centers has not been codified., Methods: A cross-sectional study was carried out on all patients attending for any reason the 24 participating centers in two non-consecutive days. Patients with fatigue filled out the Brief Fatigue Inventory (BFI) questionnaire and reported any pharmacological or non-pharmacological treatment for fatigue., Results: From October 2014 to May 2015, 1394 cancer patients agreed to participate in the study. Fatigue was referred by 866 (62.1%) of patients; its duration was > 4 months in 441 patients (50.9%). In the investigators' opinion, the most important (probable or almost sure) determinants of fatigue were reduced physical activity (271 patients), anxiety (149), pain (131), insomnia (125), anemia (123), and depression (123). Fatigue of moderate/severe intensity was reported by 43%/29.2% of patients, while usual fatigue in the last 24 h by 45%/33.1%, and the worst fatigue in the last 24 h by 33%/54.8%, respectively. Concerning the impact on quality of life, fatigue interfered moderately/severely with general activity in 30.8%/38.6% of patients, with mood in 26.1%/32.8%, with the ability to work in 27.9%/35.6%, with normal work in 26.7%/38.9%, with relationships with others in 21%/23.4% and with the ability to amuse themselves in 22.2%/33.1%. Only 117/866 patients (13.5%) received a pharmacological treatment represented by a corticosteroid in 101 patients (86.3%) while 188 patients (21.7%) received a non-pharmacological treatment such as physical exercise (120 patients, 63.8%) and various alimentary supplements (52 patients, 27.6%)., Conclusions: Cancer-related fatigue is frequently reported by oncological patients; its intensity and impact on quality of life is relevant.

The ubiquitin-proteasome complex is an important molecular target for the design of novel chemotherapeutics. This complex plays a critical role in signal transduction pathways important for tumor cell growth and survival, cell-cycle control, transcriptional regulation, and the modulation of cellular stress responses to endogenous and exogenous stimuli. The sensitivity of transformed cells to proteasome inhibitors and the successful design of treatment protocols with tolerable, albeit narrow, therapeutic indices have made proteasome inhibition a viable strategy for cancer treatment. Clinical validation of the proteasome as a molecular target was achieved with the approval of bortezomib, a boronic acid proteasome inhibitor, for the treatment of multiple myeloma and mantle cell lymphoma. Several "next-generation" proteasome inhibitors (carfilzomib and PR-047, NPI-0052, and CEP-18770) representing distinct structural classes (peptidyl epoxyketones, beta-lactones, and peptidyl boronic acids, respectively), mechanisms of action, pharmacological and pharmacodynamic activity profiles, and therapeutic indices have now entered clinical development. These agents may expand the clinical utility of proteasome inhibitors for the treatment of solid tumors and for specific non-oncological, i.e., inflammatory disease, indications as well. This chapter addresses the biology of the proteasome, the medicinal chemistry and mechanisms of action of proteasome inhibitors currently in clinical development, the preclinical and clinical pharmacological and safety profiles of bortezomib and the newer compounds against hematological and solid tumors. Future directions for research and other applications for this novel class of therapeutics agents are considered in this chapter., (2009 Elsevier Inc. All rights reserved.)

Modulating protein ubiquitination via proteasome inhibition represents a promising target for cancer therapy, because of the higher sensitivity of cancer cells to the cytotoxic effects of proteasome inhibition. Here we show that CEP-18770 is a novel orally-active inhibitor of the chymotrypsin-like activity of the proteasome that down-modulates the nuclear factor-kappaB (NF-kappaB) activity and the expression of several NF-kappaB downstream effectors. CEP-18770 induces apoptotic cell death in multiple myeloma (MM) cell lines and in primary purified CD138-positive explant cultures from untreated and bortezomib-treated MM patients. In vitro, CEP-18770 has a strong antiangiogenic activity and potently represses RANKL-induced osteoclastogenesis. Importantly, CEP-18770 exhibits a favorable cytotoxicity profile toward normal human epithelial cells, bone marrow progenitors, and bone marrow-derived stromal cells. Intravenous and oral administration of CEP-18770 resulted in a more sustained pharmacodynamic inhibition of proteasome activity in tumors relative to normal tissues, complete tumor regression of MM xenografts and improved overall median survival in a systemic model of human MM. Collectively, these findings provide evidence for the utility of CEP-18770 as a novel orally active proteasome inhibitor with a favorable tumor selectivity profile for the treatment of MM and other malignancies responsive to proteasome inhibition.

Aims and Background: To obtain proof of external validity of the visual analogue scale and re-evaluate the use of this instrument in assessing cancer patients' quality of life., Methods: Consecutive patients attending 79 Italian medical oncology and radiotherapy centers over a period of 1 week were asked to fill out both a questionnaire concerning the presence of 19 problems and a 100-mm linear visual analogue scale evaluating their quality of life. Quality of life was rated as "good" and "bad" when given a score of 70-100 and 0-30, respectively. Multifactorial logistic models were used where good and bad quality of life were correlated with explanatory variables including patient and disease characteristics and the presence or absence of the 19 problems., Results: Gender, level of education, treatment setting, Karnofsky performance status, disease extent, and the presence of 12 out of 19 problems were found to be correlated with good quality of life. A similar pattern of correlations was found with bad quality of life., Conclusions: Due to the difficulties in attaining reliable assessment of quality of life using psychometric questionnaires, the further proof of validity obtained in this study allows us to propose the re-evaluation of the role of the uniscale in measuring the quality of life of cancer patients.

Background: It has been widely shown that the provision of adequate levels of information to patients does have a positive effect on quality of life by reducing anxiety and depression levels. The aim of this study was to show how Italian cancer patients rate the information they are given and whether the use of booklets and videotapes can improve their quality of life., Patients and Methods: Cancer patients aged between 18 and 80 years who were about to receive their first chemotherapy course were randomized to fill in questionnaires on perceived quality of information, level of psychological distress, perceived severity and curability of the disease, and quality of life. The results were evaluated by means of statistical analyses., Results: Out of 328 consecutive patients enrolled in 21 cancer centers, 86-93% considered the booklets either "very useful" or "useful". The videotape was regarded as "quite" or "much" more complete than the booklets (87%). According to 81%/87% of patients, the information that had been given had improved their knowledge of the disease/chemotherapy either "a lot" or "enough"., Conclusions: The information patients receive from the oncologist was rated the highest, as long as they were devoted enough time. Booklets and videotapes can partially overcome the lack of oral information given by medical doctors. A better informed patient does help the oncologist save time.

Among the known angiogenic growth factors and cytokines implicated in the modulation of normal and pathological angiogenesis, the VEGF family (VEGF-A, VEGF-B, VEGF-C, VEGF-D) and their corresponding receptor tyrosine kinases [VEGFR-1 (Flt-1), VEGFR-2 (Flk-1, KDR), and VEGFR-3 (Flt-4)] play a paramount and indispensable role in regulating the multiple facets of the angiogenic and lymphangiogenic processes, as well as the induction of vascular permeability and inflammation. The receptor VEGFR-2/KDR is the principal one through which VEGFs exert their mitogenic, chemotactic, and vascular permeabilizing effects on the host vasculature. Increased expression of VEGFs by tumor cells and VEGFR-2/KDR and VEGFR-1/Flt-1 by the tumor-associated vasculature are a hallmark of a variety of human and rodent tumors in vivo and correlates with tumor growth rate, micro-vessel density/proliferation, tumor metastatic potential, and poorer patient prognosis in a variety of malignancies. Approaches to disrupting the VEGF/VEGFR signaling cascade range from biological agents (soluble receptors, anti-VEGF and anti-VEGFR-2 antibodies, and VEGF transcription inhibitors) to small molecule ATP competitive VEGFR inhibitors. Examples from this latter class that are currently in clinical development include compounds from distinct chemical classes such as: indolin-2-ones, anilinoquinazolines, anilinophthalazines, isothiazoles, indolo- and indenocarbazoles. The structure activity relationships, biochemical and pharmacological profile of optimized representatives from each of these classes constitute the subject matter of this review.