Summary Investigating therapeutic “outliers” that show exceptional responses to anti-cancer treatment can uncover biomarkers of drug sensitivity. We performed preclinical trials investigating primary murine acute myeloid leukemias (AMLs) generated by retroviral insertional mutagenesis in KrasG12D “knock-in” mice with the MEK inhibitor PD0325901 (PD901). One outlier AML responded and exhibited intrinsic drug resistance at relapse. Loss of wild-type (WT) Kras enhanced the fitness of the dominant clone and rendered it sensitive to MEK inhibition. Similarly, human colorectal cancer cell lines with increased KRAS mutant allele frequency are more sensitive to MAP kinase inhibition, and CRISPR-Cas9-mediated replacement of WT KRAS with a mutant allele sensitized heterozygous mutant HCT116 cells to treatment. In a prospectively characterized cohort of patients with advanced cancer, 642 of 1168 (55%) with KRAS mutations exhibited allelic imbalance. These studies demonstrate that serial genetic changes at the Kras/KRAS locus are frequent in cancer, and modulate competitive fitness and MEK dependency.

SUMMARY Early full-term pregnancy is one of the most effective natural protections against breast cancer. To investigate this effect, we have characterized the global gene expression and epigenetic profiles of multiple cell types from normal breast tissue of nulliparous and parous women, and carriers of BRCA1 or BRCA2 mutations. We found significant differences in CD44+ progenitor cells, where the levels of many stem cell-related genes and pathways, including the cell cycle regulator p27, are lower in parous women without BRCA1/BRCA2 mutations. We also noted a significant reduction in the frequency of CD44+p27+ cells in parous women, and showed using explant cultures that parity-related signaling pathways play a role in regulating the number of p27+ cells and their proliferation. Our results suggest that pathways controlling p27+ mammary epithelial cells and the numbers of these cells relate to breast cancer risk, and can be explored for cancer risk assessment and prevention.

The limitations of mammography in the detection and evaluation of invasive lobular carcinoma (ILC) have long been recognized, presenting real clinical challenges in treatment planning for these tumors. However, advances in mammography, ultrasound, and magnetic resonance imaging present opportunities to improve the diagnosis and preoperative assessment of ILC. The evidence supporting the performance of each imaging modality will be reviewed, specifically as it relates to the pathology of ILC and its subtypes. Further, we will discuss emerging technologies that may be employed to enhance the detection rate and ultimately result in more effective screening and staging of ILC.

Key Points N-Ras expression is essential for the proliferative advantage of acute myeloid leukemias with oncogenic NRAS/Nras mutations. Mitogen-activated protein kinase kinase inhibition prolongs survival in Nras-mutant AML by reducing proliferation, but fails to undergo apoptosis.

The palmitoylation/depalmitoylation cycle of posttranslational processing is a potential therapeutic target for selectively inhibiting the growth of hematologic cancers with somatic NRAS mutations. To investigate this question at the single-cell level, we constructed murine stem cell virus vectors and assayed the growth of myeloid progenitors. Whereas cells expressing oncogenic N-Ras G12D formed cytokine-independent colonies and were hypersensitive to GM-CSF, mutations within the N-Ras hypervariable region induced N-Ras mislocalization and attenuated aberrant progenitor growth. Exposing transduced hematopoietic cells and bone marrow from Nras and Kras mutant mice to the acyl protein thioesterase inhibitor palmostatin B had similar effects on protein localization and colony growth. Importantly, palmostatin B-mediated inhibition was selective for Nras mutant cells, and we mapped this activity to the hypervariable region. These data support the clinical development of depalmitoylation inhibitors as a novel class of rational therapeutics in hematologic malignancies with NRAS mutations. IntroductionRas proteins regulate cell fate by cycling between active GTPbound and inactive GDP-bound conformations (Ras-GTP and Ras-GDP). RAS genes encode 4 proteins (N-Ras, H-Ras, K-Ras4A, and K-Ras4B) that have identical guanine nucleotide and effector binding domains but diverge substantially within the hypervariable region (HVR). 1,2 Prenylation of the C-terminal cysteine and palmitoylation of other cysteines within the HVR of H-Ras and N-Ras induce a dynamic cycle of depalmitoylation and repalmitoylation that regulates subcellular trafficking. By contrast, K-Ras4B localizes to the plasma membrane (PM) by a mechanism that does not involve palmitoylation. 1 Perturbation of palmitate turnover leads to a nonspecific distribution of H-and N-Ras to endomembranes and decreases signaling from the PM. 3 This observation suggests that interfering with depalmitoylation might selectively reduce the growth of cancer cells with NRAS mutations, as normal K-Ras4B function would be preserved. Inhibiting oncogenic N-Ras signaling is particularly relevant in hematologic malignancies where NRAS is mutated more frequently than KRAS. [4][5][6][7][8][9] Acyl protein thioesterase 1 (APT1) catalyzes Ras depalmitoylation. 10 Dekker et al 10 recently developed palmostatin B, a small molecule inhibitor with activity against APT1 that disrupted normal H-Ras subcellular localization and attenuated signaling in fibroblasts transformed with oncogenic Hras. Here we present genetic, cell biologic, and biochemical data with in vitro studies of palmostatin B that support targeting the depalmitoylation/ repalmitoylation cycle in hematologic cancers characterized by oncogenic NRAS mutations. MethodsNras and Kras alleles containing an N terminal green fluorescent protein (GFP) marker were cloned into the murine stem cell virus (MSCV) vector with expression driven by the internal ribosomal entry site. 11,12 Retrovirally transduced E14.5 fetal liver cells from inbred ...

Increased FDG uptake is observed in medulloblastoma and is correlated negatively with survival.

Secondary hemophagocytic lymphohistiocytosis (sHLH) is a reactive, proliferative disorder of the immune system resulting in lymphohistiocytic proliferation, hemophagocytosis, and cytokine dysregulation. The most common infectious trigger in sHLH is Epstein-Barr virus (EBV-HLH). Current treatment protocols for EBV-HLH have a cure rate of approximately 75%; however, there are significant toxicities associated with these therapies. We present two patients with EBV-HLH who experienced spontaneous resolution of their disease prior to the initiation of therapy, suggesting there may be a subgroup of patients with EBV-HLH who do well with conservative management and can avoid potentially toxic therapies.

The management of in situ lesions ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS) continues to evolve. These diagnoses now comprise a large burden of mammographically diagnosed cancers, and with a global trend towards more population-based screening, the incidence of these lesions will continue to rise. Because outcomes following treatment for DCIS and LCIS are excellent, there is emerging controversy about what extent of treatment is optimal for both diseases. Here we review the current approaches to the diagnosis and treatment of both DCIS and LCIS. In addition, we will consider potential directions for future management of these lesions.