The phosphatidylinositol 3-kinase signal transduction pathway members are often activated in tumor samples from patients with non-Hodgkin's lymphoma (NHL). Everolimus is an oral agent that targets the raptor mammalian target of rapamycin (mTORC1). The goal of this trial was to learn the antitumor activity and toxicity of single-agent everolimus in patients with relapsed/refractory aggressive NHL. Patients received everolimus 10 mg PO daily. Response was assessed after two and six cycles, and then every three cycles until progression. A total of 77 patients with a median age of 70 years were enrolled. Patients had received a median of three previous therapies and 32% had undergone previous transplant. The overall response rate (ORR) was 30% (95% confidence interval: 20–41%), with 20 patients achieving a partial remission and 3 a complete remission unconfirmed. The ORR in diffuse large B cell was 30% (14/47), 32% (6/19) in mantle cell and 38% (3/8) in follicular grade 3. The median duration of response was 5.7 months. Grade 3 or 4 anemia, neutropenia and thrombocytopenia occurred in 14, 18 and 38% of patients, respectively. Everolimus has single-agent activity in relapsed/refractory aggressive NHL and provides proof-of-concept that targeting the mTOR pathway is clinically relevant.

PD-L1 expression in primary clear cell renal cell carcinoma (ccRCC) increases the likelihood of response to anti-PD-1 inhibition, but fails to identify all responders. We hypothesized that PD-L1 levels assessed in randomly selected areas of the primary tumors may not accurately reflect expression levels in metastatic lesions, which are the target of systemic therapy. Therefore, we compared PD-L1 expression in a series of primary ccRCC and their metastases. Tissue blocks from 53 primary ccRCCs and 76 corresponding metastases were retrieved. Areas with predominant and highest nuclear grade were selected. Slides were immunostained with a validated anti-PD-L1 antibody (405.9A11). Membranous expression in tumor cells was quantified using H-score. Expression in tumor-infiltrating mononuclear cells (TIMC) was quantified using a combined score. Discordant tumor cell PD-L1 staining between primary tumors and metastases was observed in 11/53 cases (20.8%). Overall, tumor cell PD-L1 levels were not different in primary tumors and metastases (p=0.51). Tumor cell PD-L1 positivity was associated with higher T stage (p=0.03) and higher Fuhrman Nuclear Grade (FNG) (p<0.01). Within individual lesions, PD-L1 positivity was heterogeneous and almost exclusively detected in high nuclear grade areas (p<0.001). No difference was found in PD-L1 levels in TIMCs between primary tumors and metastases (p=0.82). Heterogeneity of PD-L1 expression in ccRCC suggests that its assessment as predictive biomarker for PD-1 blockade may require analysis of metastatic lesions. Notably, since PD-L1 expression was mostly detected in high nuclear grade areas, to avoid false negative results, these areas should be specifically selected for assessment.

The mammalian target of rapamycin (mTOR) has emerged as an important therapeutic target for diffuse large B-cell lymphoma (DLBCL), as recent studies have demonstrated that 30% of relapsed patients respond to mTOR inhibitors. Why some lymphomas are resistant is incompletely understood. In the present study, we demonstrated that rapamycin inhibits mTORC1 in DLBCL lines and primary tumors but is minimally cytotoxic. Subsequent investigations revealed that rapamycin also activated eIF4E and the mTORC2 target Akt, suggesting a potential mechanism of rapamycin resistance. IntroductionDiffuse large B-cell lymphoma (DLBCL), an aggressive form of non-Hodgkin lymphoma (NHL), is the most common type of lymphoma in the United States. With rituximab-based chemoimmunotherapy such as rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, approximately 60% of DLBCL patients are cured. 1,2 Salvage chemotherapy followed by stem cell transplantation is able to produce durable remissions in a minority of relapsed patients, and improved therapy is required for those who relapse after second-line treatment.Because deregulation of the PI3 kinase (PI3K)/mTOR pathway occurs in many human diseases, 3,4 targeting the mTOR pathway with small molecule inhibitors has become an intense area of research. Key components of this pathway, including Akt and mTOR, regulate cell growth and survival. 5 The mTOR kinase exists as 2 complexes. The rapamycin-sensitive mTOR complex 1 (mTORC1 or raptor/mTOR), consists of mTOR, raptor, and mLST8. mTORC1 regulates translation initiation through 2 distinct pathways: ribosomal p70 S6 kinase (p70S6K) and eukaryotic translation initiation factor 4E (eIF4E) binding proteins (4E-BPs). In one pathway, mTORC1 phosphorylates and activates the ribosomal protein S6. In the second pathway, mTORC1 directly phosphorylates 4E-BP1 causing its dissociation from the translation initiation factor eIF4E. This allows eIF4E to stimulate cap-dependent RNA translation. In the absence of mTORC1 activation, 4EBP1 binds tightly to eIF4E, preventing it from binding to 5Ј-capped mRNA. 6 The mTOR complex 2 (mTORC2 or rictor/mTOR), which contains mTOR, rictor, and mLST8, is rapamycin insensitive and functions to regulate the survival kinase Akt by phosphorylation of serine 473. 5 Recent clinical trials of the mTORC1 inhibitors temsirolimus and everolimus, both analogues of the parent compound rapamycin, have demonstrated overall response rates (ORRs) of approximately 30% for relapsed DLBCL. 7 This single-agent activity of mTOR inhibitors in heavily pretreated DLBCL patients highlights the importance of the PI3K/mTOR pathway in these cells. To exploit the sensitivity of lymphomas to mTOR inhibitors through effective therapies, it is important to understand the mechanistic basis for resistance of DLBCL to mTOR inhibition.Histone deacetylase inhibitors (HDIs) have emerged as a potentially promising new class of anticancer drugs. The inhibition of histone deacetylases (HDACs) by HDIs results in increased gene-specific his...