Recurrent Spontaneous Pneumothorax Secondary to Marijuana and Tobacco Abuse.

Primary spontaneous pneumothorax occurs in patients without apparent clinical lung disease, with a higher incidence in tall, thin males between the ages of 10 and 30. Tension pneumothorax is a life-threatening condition that can develop within minutes due to progressive air accumulation in the pleural space; mechanical pressure can lead to significant cardiorespiratory compromise. Tobacco association with a higher incidence of spontaneous pneumothorax has been well documented, but marijuana and spontaneous pneumothorax connection has not been well studied. However, it has been observed that patients who use marijuana and tobacco simultaneously have a higher incidence of spontaneous tension and larger pneumothoraces, as well as longer postoperative stay and higher recurrence than cigarette-only users. We present a case of a 26-year-old young male with a history only significant for excessive tobacco and marijuana smoking who developed multiple recurrent spontaneous pneumothorax and had to undergo right-sided video-assisted thoracoscopic surgery (VATS) with minimally invasive thoracotomy and had a prolonged hospital stay. With our case report, we hope to add to the evidence the effects of combined marijuana and tobacco smoking on bullous lung disease and pneumothorax while emphasizing the importance of conducting a detailed substance use history in patients with spontaneous pneumothorax.

Selinexor in Combination with R-CHOP for Frontline Treatment of Non-Hodgkin Lymphoma: Results of a Phase I Study.

PURPOSE: The nuclear exporter protein exportin-1 (XPO1) is overexpressed in non-Hodgkin lymphoma (NHL) and correlates with poor prognosis. We evaluated enhancing R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) activity in NHL by targeted inhibition of XPO1 using the selective inhibitor of nuclear export (SINE) compounds. PATIENTS AND METHODS: We evaluated the antitumor activity of SINE compounds in combination with CHO chemotherapy in vitro and in vivo. Newly diagnosed NHL patients in a phase I dose-escalation study received R-CHOP for 6 cycles with weekly selinexor (60, 80, and 100 mg), then selinexor maintenance therapy for one year. RT-PCR, Western blotting, and RNA sequencing were performed on patient blood samples. RESULTS: SINE compounds synergized with CHO in vitro in NHL cell lines and in vivo in our murine xenograft model. In our phase I study, selinexor was dosed at 60 mg (n = 6) and 80 mg (n = 6). The most common adverse events (AE) among 12 patients were fatigue (67%) and nausea (100%). Grade 3-4 AEs were infrequent. Ten evaluable patients had an overall response rate of 100% and complete remission rate of 90% with sustained remissions (median follow-up: 476 days). Maximally tolerated dose was not reached; however, the recommended phase II dose was 60 mg selinexor weekly after evaluating tolerability and discontinuation rates for each dose cohort. Analysis of patient blood samples revealed downregulation of XPO1 and several prosurvival markers. CONCLUSIONS: SINE compounds enhance the activity of CHO in vitro and in vivo. Selinexor in combination with R-CHOP was generally well tolerated and showed encouraging efficacy in NHL (NCT03147885).

PAK4 and NAMPT as Novel Therapeutic Targets in Diffuse Large B-Cell Lymphoma, Follicular Lymphoma, and Mantle Cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL), grade 3b follicular lymphoma (FL), and mantle cell lymphoma (MCL) are aggressive non-Hodgkin's lymphomas (NHL). Cure rates are suboptimal and novel treatment strategies are needed to improve outcomes. Here, we show that p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyl transferase (NAMPT) is critical for lymphoma subsistence. Dual targeting of PAK4-NAMPT by the Phase I small molecule KPT-9274 suppressed cell proliferation in DLBCL, FL, and MCL. Growth inhibition was concurrent with apoptosis induction alongside activation of pro-apoptotic proteins and reduced pro-survival markers. We observed NAD suppression, ATP reduction, and consequent cellular metabolic collapse in lymphoma cells due to KPT-9274 treatment. KPT-9274 in combination with standard-of-care chemotherapeutics led to superior inhibition of cell proliferation. In vivo, KPT-9274 could markedly suppress the growth of WSU-DLCL2 (DLBCL), Z-138, and JeKo-1 (MCL) sub-cutaneous xenografts, and a remarkable increase in host life span was shown, with a 50% cure of a systemic WSU-FSCCL (FL) model. Residual tumor analysis confirmed a reduction in total and phosphorylated PAK4 and activation of the pro-apoptotic cascade. This study, using various preclinical experimental models, demonstrates the therapeutic potential of targeting PAK4-NAMPT in DLBCL, FL, and MCL. The orally bioavailable, safe, and efficacious PAK4-NAMPT dual inhibitor KPT-9274 warrants further clinical investigation.

Pre-clinical anti-tumor activity of Bruton's Tyrosine Kinase inhibitor in Hodgkin's Lymphoma cellular and subcutaneous tumor model.

Bruton's Tyrosine Kinase (BTK) is a member of the TEC family and plays a central role in B-cell signaling, activation, proliferation and differentiation. Here we evaluated the impact of BTK inhibitor Ibrutinib on a panel of HL models in vitro and in vivo. Ibrutinib suppressed viability and induced apoptosis in 4 HL cell lines in a dose and time dependent manner. Molecular analysis showed induction of both apoptotic and autophagy markers. Ibrutinib treatment resulted in suppression of BTK and other downstream targets including PI3K, mTOR and RICTOR. Ibrutinib given at 50 mg/kg p.o daily for three weeks caused statistically significant inhibition of HL cell line derived subcutaneous xenografts (p < 0.01) in ICR-SCID mice. Molecular analysis of residual tumor tissue revealed down-regulation of BTK; its related markers and autophagy markers. Our studies are the first showing in vitro and in vivo action of BTK inhibition in classical HL. A phase II study examining the activity of ibrutinib in relapsed or refractory HL is currently enrolling (NCT02824029).

Targeting XPO1 and PAK4 in 8505C Anaplastic Thyroid Cancer Cells: Putative Implications for Overcoming Lenvatinib Therapy Resistance.

Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) that shows improved median progression-free survival (PFS) in patients with thyroid carcinomas. However, virtually all patients ultimately progress, indicating the need for a better understanding of the mechanisms of resistance. Here, we examined the molecular profile of anaplastic thyroid cancer cells (8505C) exposed to lenvatinib and found that long-term exposure to lenvatinib caused phenotypic changes. Consistent with change toward mesenchymal morphology, activation of pro-survival signaling, nuclear exporter protein exportin 1 (XPO1) and Rho GTPase effector p21 activated kinases (PAK) was also observed. RNA-seq analysis showed that prolonged lenvatinib treatment caused alterations in numerous cellular pathways and several oncogenes such as CEACAM (carcinoembryonic antigen-related cell adhesion molecule) and NUPR1 (Nuclear protein 1) were also upregulated. Further, we evaluated the impact of XPO1 and PAK4 inhibition in the presence or absence of lenvatinib. Targeted inhibition of XPO1 and PAK4 could sensitize the 8505C cells to lenvatinib. Both XPO1 and PAK4 inhibitors, when combined with lenvatinib, showed superior anti-tumor activity in 8505C sub-cutaneous xenograft. These studies bring forward novel drug combinations to complement lenvatinib for treating anaplastic thyroid cancer. Such combinations may possibly reduce the chances of lenvatinib resistance in thyroid cancer patients.

Rho GTPase effectors and NAD metabolism in cancer immune suppression.

INTRODUCTION: Sustained proliferative signaling and de-regulated cellular bioenergetics are two of the chief hallmarks of cancer. Alterations in the Ras pathway and its downstream effectors are among the major drivers for uncontrolled cell growth in many cancers. The GTPases are one of the signaling molecules that activate crucial signal transducing pathways downstream of Ras through several effector proteins. The GTPases (GTP bound) interact with several effectors and modulate a number of different biological pathways including those that regulate cytoskeleton, cellular motility, cytokinesis, proliferation, apoptosis, transcription and nuclear signaling. Similarly, the altered glycolytic pathway, the so-called 'Warburg effect', rewires tumor cell metabolism to support the biosynthetic requirements of uncontrolled proliferation. There exists strong evidence for the critical role of the glycolytic pathway's rate limiting enzymes in promoting immunosuppression. Areas covered: We review the emerging roles of GTPase effector proteins particularly the p21 activated kinase 4 (PAK4) and nicotinamide biosynthetic pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT) as signaling molecules in immune surveillance and the immune response. Expert opinion: In this expert opinion article we highlight the recent information on the role of GTPases and the metabolic enzymes on the immune microenvironment and propose some unique immune therapeutic opportunities.