Phase I Study of the Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (TAK-924/MLN4924) in Patients with Advanced Solid Tumors.

Purpose: To determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with advanced nonhematologic malignancies.

Experimental Design: Pevonedistat was administered via 60-minute intravenous infusion on days 1 to 5 (schedule A, n = 12), or days 1, 3, and 5 (schedules B, n = 17, and C, n = 19) of 21-day cycles. Schedule B included oral dexamethasone 8 mg before each pevonedistat dose.

RB-loss puts focus on Myc.

Activator E2Fs and Myc cooperate as master regulators of proliferation. A new study sheds light on one of the fundamental questions in cancer biology: how do oncogenic changes, such as Retinoblastoma (RB)-mutation, modify E2F and Myc activity?

Investigation of the Lack of Angiogenesis in the Formation of Lymph Node Metastases.

Background: To date, antiangiogenic therapy has failed to improve overall survival in cancer patients when used in the adjuvant setting (local-regional disease with no detectable systemic metastasis). The presence of lymph node metastases worsens prognosis, however their reliance on angiogenesis for growth has not been reported.

Methods: Here, we introduce a novel chronic lymph node window (CLNW) model to facilitate new discoveries in the growth and spread of lymph node metastases.

Molecular stratification of metastatic melanoma using gene expression profiling: Prediction of survival outcome and benefit from molecular targeted therapy.

Melanoma is currently divided on a genetic level according to mutational status. However, this classification does not optimally predict prognosis. In prior studies, we have defined gene expression phenotypes (high-immune, pigmentation, proliferative and normal-like), which are predictive of survival outcome as well as informative of biology.

Functional analysis of a chromosomal deletion associated with myelodysplastic syndromes using isogenic human induced pluripotent stem cells.

Chromosomal deletions associated with human diseases, such as cancer, are common, but synteny issues complicate modeling of these deletions in mice. We use cellular reprogramming and genome engineering to functionally dissect the loss of chromosome 7q (del(7q)), a somatic cytogenetic abnormality present in myelodysplastic syndromes (MDS). We derive del(7q)- and isogenic karyotypically normal induced pluripotent stem cells (iPSCs) from hematopoietic cells of MDS patients and show that the del(7q) iPSCs recapitulate disease-associated phenotypes, including impaired hematopoietic differentiation.

MITF Modulates Therapeutic Resistance through EGFR Signaling.

Response to targeted therapies varies significantly despite shared oncogenic mutations. Nowhere is this more apparent than in BRAF (V600E)-mutated melanomas where initial drug response can be striking and yet relapse is commonplace. Resistance to BRAF inhibitors have been attributed to the activation of various receptor tyrosine kinases (RTKs), although the underlying mechanisms have been largely uncharacterized.

Mesenchymal cell contributions to the stem cell niche.

Mesenchymal stromal cells (MSCs) are heterogeneous and primitive cells discovered first in the bone marrow (BM). They have putative roles in maintaining tissue homeostasis and are increasingly recognized as components of stem cell niches, which are best defined in the blood. The absence of in vivo MSC markers has limited our ability to track their behavior in vivo and draw comparisons with in vitro observations.

Cardiac and inflammatory biomarkers do not correlate with volume of heart or lung receiving radiation.

Background: Thoracic and cardiac irradiation increases the risk of pulmonary and cardiovascular disease. In addition, radiation, often in combination with chemotherapy, can cause treatment-related pneumonitis. Previously, we showed that the common marker for cardiac damage, troponin T, was not elevated by chemoradiation [Lung Cancer 62:351-355, 2008].

HDAC6 inhibitors modulate Lys49 acetylation and membrane localization of β-catenin in human iPSC-derived neuronal cells.

We examined the effects of isoform-specific histone deacetylase (HDAC) inhibitors on β-catenin posttranslational modifications in neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (iPSCs). β-catenin is a multifunctional protein with important roles in the developing and adult central nervous system. Activation of the Wnt pathway results in stabilization and nuclear translocation of β-catenin, resulting in activation of multiple target genes.

EPHA2 is a mediator of vemurafenib resistance and a novel therapeutic target in melanoma.

Unlabelled: BRAF(V600E) is the most common oncogenic lesion in melanoma and results in constitutive activation of the MAPK pathway and uncontrolled cell growth. Selective BRAF inhibitors such as vemurafenib have been shown to neutralize oncogenic signaling, restrain cellular growth, and improve patient outcome. Although several mechanisms of vemurafenib resistance have been described, directed solutions to overcome these resistance lesions are still lacking.

Peripheral residence of naïve CD4 T cells induces MHC class II-dependent alterations in phenotype and function.

Background: As individual naïve CD4 T lymphocytes circulate in the body after emerging from the thymus, they are likely to have individually varying microenvironmental interactions even in the absence of stimulation via specific target recognition. It is not clear if these interactions result in alterations in their activation, survival and effector programming. Naïve CD4 T cells show unimodal distribution for many phenotypic properties, suggesting that the variation is caused by intrinsic stochasticity, although underlying variation due to subsets created by different histories of microenvironmental interactions remains possible.

BAP1 has a survival role in cutaneous melanoma.

Although the pattern of BAP1 inactivation in ocular melanoma specimens and in the BAP1 cutaneous melanoma (CM)/ocular melanoma predisposition syndrome suggests a tumor suppressor function, the specific role of this gene in the pathogenesis of CM is not fully understood. We thus set out to characterize BAP1 in CM and discovered an unexpected pro-survival effect of this protein. Tissue and cell lines analysis showed that BAP1 expression was maintained, rather than lost, in primary melanomas compared with nevi and normal skin.

The melanoma revolution: from UV carcinogenesis to a new era in therapeutics.

Melanoma, the deadliest form of skin cancer, is an aggressive disease that is rising in incidence. Although melanoma is a historically treatment-resistant malignancy, in recent years unprecedented breakthroughs in targeted therapies and immunotherapies have revolutionized the standard of care for patients with advanced disease. Here, we provide an overview of recent developments in our understanding of melanoma risk factors, genomics, and molecular pathogenesis and how these insights have driven advances in melanoma treatment.

Tanning as a substance abuse.

While few people would deny the appeal of a day in the sun there are some who seem to take it too far. In recent years the concept of 'tanning addiction' has become popular and several studies have supported the notion of viewing exposure to UV radiation as a form of substance abuse. In this article we will review some of the literature on sun seeking behavior.

Epidermal, sebaceous, and melanocytic nevoid proliferations are spectrums of mosaic RASopathies.

Growing evidence demonstrates that various nevoid proliferations such as keratinocytic epidermal nevi and nevus sebaceous result from somatic mosaicism. Many of the mutations identified have been within the RAF/RAS/MAPK pathway, hence supporting the previously introduced term "mosaic RASopathy" for these nevi. In this issue, Kinsler et al.

Delineating the mTOR kinase pathway using a dual TORC1/2 inhibitor, AZD8055, in multiple myeloma.

Despite promising preclinical results with mTOR kinase inhibitors in multiple myeloma, resistance to these drugs may arise via feedback activation loops. This concern is especially true for insulin-like growth factor 1 receptor (IGF1R), because IGF1R signaling is downregulated by multiple AKT and mTOR feedback mechanisms. We have tested this hypothesis in multiple myeloma using the novel selective mTOR kinase inhibitor AZD8055.

Current status and future directions of molecularly targeted therapies and immunotherapies for melanoma.

Key molecular and immunological insights over the past decade have radically changed the face of therapy in melanoma. Whereas 5 years ago, treatment for advanced melanoma was restricted to the alkylating agent dacarbazine and the immunostimulants interleukin-2 and interferon-α-2b, today the therapeutic menu includes precise therapies that target key determinants in oncogenic pathways and immune checkpoints. In this chapter, we will review the current status and future directions of targeted therapies for melanoma directed at mitogen-activated pathways and immune checkpoints.

Skin β-endorphin mediates addiction to UV light.

UV light is an established carcinogen, yet evidence suggests that UV-seeking behavior has addictive features. Following UV exposure, epidermal keratinocytes synthesize proopiomelanocortin (POMC) that is processed to melanocyte-stimulating hormone, inducing tanning. We show that, in rodents, another POMC-derived peptide, β-endorphin, is coordinately synthesized in skin, elevating plasma levels after low-dose UV.

Circulating tumour cells-monitoring treatment response in prostate cancer.

The availability of new therapeutic options for the treatment of metastatic castration-resistant prostate cancer (mCRPC) has heightened the importance of monitoring and assessing treatment response. Accordingly, there is an unmet clinical need for reliable biomarkers that can be used to guide therapy. Circulating tumour cells (CTCs) are rare cells that are shed from primary and metastatic tumour deposits into the peripheral circulation, and represent a means of performing noninvasive tumour sampling.

Long-term results of Phase II study of high dose photon/proton radiotherapy in the management of spine chordomas, chondrosarcomas, and other sarcomas.

Background: Negative surgical margins are uncommon for spine sarcomas; hence, adjuvant radiotherapy (RT) may be recommended but tumor dose may be constrained by spinal cord, nerve, and viscera tolerance.

Methods: Prospective Phase II clinical trial incorporating high dose RT. Eligible patients had primary or locally recurrent thoracic, lumbar, and/or sacral spine/paraspinal chordomas or sarcomas.

Neural correlates of chemotherapy-related cognitive impairment.

Cancer survivors frequently experience cognitive deficits following chemotherapy. The most commonly affected functions include memory, attention and executive control. The present paper reviews animal research and clinical studies including event-related potential (ERP) and neuroimaging investigations of chemotherapy-related changes of brain structure and function.

Preclinical activity of the oral proteasome inhibitor MLN9708 in Myeloma bone disease.

Purpose: MLN9708 (ixazomib citrate), which hydrolyzes to pharmacologically active MLN2238 (ixazomib), is a next-generation proteasome inhibitor with demonstrated preclinical and clinical antimyeloma activity, but yet with an unknown effect on myeloma bone disease. Here, we investigated its bone anabolic and antiresorptive effects in the myeloma setting and in comparison with bortezomib in preclinical models.

Experimental Design: The in vitro effect of MLN2238 was tested on osteoclasts and osteoclast precursors from healthy donors and patients with myeloma, and on osteoprogenitors derived from bone marrow mesenchymal stem cells also from both origins.

Efficacy and safety of ixabepilone plus capecitabine in elderly patients with anthracycline- and taxane-pretreated metastatic breast cancer.

Objectives: Data on chemotherapy regimens in elderly patients with metastatic breast cancer (MBC) are limited. The aim of this retrospective pooled analysis was to determine efficacy and safety of ixabepilone plus capecitabine versus capecitabine alone in patients with MBC aged ≥ 65 years.

Materials And Methods: A total of 1973 patients with MBC previously treated with or resistant to anthracyclines and taxanes were randomized in two open-label, multinational, phase 3 studies (study 046 and study 048).

Vemurafenib synergizes with nutlin-3 to deplete survivin and suppresses melanoma viability and tumor growth.

Purpose: For patients with advanced melanoma, primary and secondary resistance to selective BRAF inhibition remains one of the most critically compelling challenges. One rationale argues that novel biologically informed strategies are needed to maximally cripple melanoma cells up front before compensatory mechanisms emerge. As p53 is uncommonly mutated in melanoma, restoration of its function represents an attractive adjunct to selective BRAF inhibition.