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IDH mutations in cancer and progress toward development of targeted therapeutics.

Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are key metabolic enzymes, converting isocitrate to α-ketoglutarate (αKG).IDH1andIDH2mutations have been identified in multiple tumor types, including gliomas and myeloid malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Here we provide an overview of the function of normal and mutated IDH, discuss the role ofIDHmutations in tumorigenesis and progression and review the key clinical considerations when treatingIDH-mutated tumors based on emerging clinical data from mutant IDH1/2 inhibitor trials. IDH1andIDH2mutations confer neomorphic activity in the mutant protein, resulting in the conversion of αKG to the oncometabolite, D-2-hydroxyglutarate (2-HG). The subsequent accumulation of 2-HG results in epigenetic dysregulation via inhibition of αKG-dependent histone and DNA demethylases, and a block in cellular differentiation. There is growing preclinical and clinical evidence suggesting thatIDHmutations are involved in neoplasia. Furthermore, preclinical studies assessing small molecule inhibitors of mutant IDH1/2 enzymes have provided proof of concept that this approach decreases intracellular 2-HG levels, reverses epigenetic dysregulation and induces cellular differentiation. Phase I studies of mutant IDH inhibitors are currently ongoing in patients with IDH-mutant hematologic and solid tumors, with early data in hematologic tumors suggesting a manageable safety profile as well as clinical benefit, with a mechanism of action based on differentiation of malignant cells. Inhibition of mutant IDH shows promise as a treatment approach in hematologic malignancies, with further development ongoing in solid tumors and glioma. The mutant IDH inhibitors may have clinical utility both as single agents and in combination strategies that target additional oncogenic pathways.
© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].

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Addressing the elephant in the room, therapeutic resistance in non-small cell lung cancer, with epigenetic therapies.

Like Chinese boxes nesting inside each other, the classification of non-small cell lung cancer (NSCLC) is subdivided into smaller and smaller subtypes on the basis of histological and molecular attributes. The latter characterizes NSCLC by its molecular alterations and the identification of inhibitors that target these cancer-specific &quot;driver&quot; mutations. Despite the initial promise of precision-guided therapies to inhibit a finer and finer array of molecular subcategories, despite even the curative potential of immunotherapeutic checkpoint blockade, in particular, casualties still abound and true clinical success stories are few and far between; the ever-present, if sometimes unmentioned, &quot;elephant in the room&quot;, is the acquisition of resistance, which, sooner or later, rears its ugly head to undermine treatment success and shorten survival. Emerging data suggests that epigenetic therapies are able to reprogram the aberrant tumor-associated epigenome and ‘tame the beast of resistance’, thereby prolonging survival. This article reviews the role of epigenetic dysregulation in NSCLC, explores PFS2 as a possible surrogate endpoint, briefly mentions possible biomarkers and highlights combinatorial treatment epigenetic strategies to &quot;prime&quot; tumors and reverse resistance.

T cells conditioned with MDSC show an increased anti-tumor activity after adoptive T cell based immunotherapy.

The success of adoptive T cell-based immunotherapy (ACT) in cancer is limited in part by the accumulation of myeloid-derived suppressor cells (MDSC), which block several T cell functions, including T cell proliferation and the expression of various cytotoxic mediators. Paradoxically, the inhibition of CD8+ T cell differentiation into cytotoxic populations increased their efficacy after ACT into tumor-bearing hosts. Therefore, we aimed to test the impact of conditioning CD8+ T cells with MDSC on their differentiation potential and ACT efficacy. Our results indicate that MDSC impaired the progression of CD8+ T cells into effector populations, without altering their activation status, production of IL-2, or signaling through the T cell receptor. In addition, culture of CD8+ T cells with MDSC resulted in an increased ACT anti-tumor efficacy, which correlated with a higher frequency of the transferred T cells and elevated IFNγ production. Interestingly, activated CD62L+ CD8+ Tcells were responsible for the enhanced anti-tumor activity showed by MDSC-exposed T cells. Additional results showed a decreased protein synthesis rate and lower activity of the mammalian/mechanistic target of rapamycin (mTOR) in T cells conditioned with MDSC. Silencing of the negative mTOR regulator tuberous sclerosis complex-2 in T cells co-cultured with MDSC restored mTOR activity, but resulted in T cell apoptosis. These results indicate that conditioning of T cells with MDSC induces stress survival pathways mediated by a blunted mTOR signaling, which regulated T cell differentiation and ACT efficacy. Continuation of this research will enable the development of better strategies to increase ACT responses in cancer.

Clinical application of PET/MRI in oncology.

Hybrid imaging with integrated positron emission tomography (PET) and magnetic resonance imaging (MRI) combines the advantages of the high-resolution anatomic data from MRI and functional imaging data from PET, and has the potential to improve the diagnostic evaluation of various types of cancers. The clinical oncologic applications of this newest hybrid imaging technology are evolving and substantial efforts are underway to define the role of PET/MRI in routine clinical use. The current published literature suggests that PET/MRI may play an important role in the evaluation of patients with certain types of malignancies, involving anatomic locations such as the pelvis and the liver. The purpose of this article is to review the current published PET/MRI literature in specific body oncologic applications. In addition, PET/MRI protocols and some of the technical issues of this hybrid imaging will be briefly discussed. J. Magn. Reson. Imaging 2016.
© 2016 Wiley Periodicals, Inc.

Idiopathic Acquired Osteosclerosis in a Middle-Aged Woman with Systemic Lupus Erythematosus.

Widely distributed osteosclerosis is an unusual radiographic finding with multiple causes. A 42-year-old pre-menopausal Spanish woman gradually acquired dense bone diffusely affecting her axial skeleton and focally affecting her proximal long bones. Systemic lupus erythematosus diagnosed in adolescence had been well controlled. She had not fractured or received antiresorptive therapy, and was hepatitis C virus antibody negative. Family members had low bone mass. Lumbar spine BMD measured by dual-photon absorptiometry at age 17 years, while receiving glucocorticoids, was 79% the average value of age-matched controls. From ages 30 to 37 years, DXA BMD z-scores steadily increased in her lumbar spine from +3.8 to +7.9, and femoral neck from -1.4 to -0.7. Serum calcium and phosphorus levels were consistently normal, 25OHD &lt;20 ng/mL, and PTH sometimes slightly increased. Her reduced eGFR was 38-55 mls/min. Hypocalciuria likely reflected positive mineral balance. During increasing BMD, turnover markers (serum bone-ALP, PINP, osteocalcin, and CTX, and urinary NTX) were 1.6- to 2.8-fold above the reference limits. Those of bone formation seemed increased more than those of resorption. FGF-23 was slightly elevated, perhaps from kidney disease. Serum OPG and TGFβ1 levels were normal, but sclerostin (SOST) and RANKL were elevated. Serum multiplex biomarker profiling confirmed a high level of SOST and RANKL, whereas DKK-1 seemed low. Matrix metalloproteinases-3 and -7 were elevated. Iliac crest biopsy revealed tetracycline labels, no distinction between thick trabeculae and cortical bone, absence of peritrabecular fibrosis, few osteoclasts, and no mastocytosis. Then, for the past three years, BMD z-scores steadily decreased. Skeletal fluorosis, mastocytosis, myelofibrosis, hepatitis C-associated osteosclerosis, multiple myeloma, and aberrant phosphate homeostasis did not explain her osteosclerosis. Mutation analysis of the LRP5, LRP4, SOST, and osteopetrosis genes was negative. Microarray showed no notable copy number variation. Perhaps her osteosclerosis reflected an interval of autoimmune-mediated resistance to SOST and/or RANKL. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.