Case Report

Bortezomib-Contained Chemotherapy and Thalidomide Combined With CHOP (Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) Play Promising Roles in Plasmablastic Lymphoma: A Case Report and Literature Review

Plasmablastic lymphoma (PBL) is a CD20-negative large B-cell lymphoma with a plasmacytic phenotype and a dismal prognosis, which has been defined as a distinct entity only in the 2008 WHO Classification of Haematopoietic and Lymphoid Tissue and confirmed in the 2017 Edition. Current knowledge of the biological, clinical and prognostic features of PBL is mostly limited, resulting in diagnostic issues, as well as in lack of standard of care and effective therapeutic options. PBL commonly affects the oral cavity of HIV-positive individuals, however the gastrointestinal (GI) tract is the most common extraoral site, and in this location most patients are HIV-negative. In this review, we focus on the clinical, morphological and prognostic features of PBL arising in the GI tract, in order to improve knowledge on this rare, but aggressive disease.

Hepatocellular carcinoma which is featured with the extensive vascularization is the third most frequent cause of cancer-related deaths with limited therapeutic options, particularly for advanced disease. Cobimetinib, a MEK inhibitor, has been approved for the treatment of melanomas with a BRAF mutation. In this work, we investigated the efficacy of cobimetinib in sensitive and resistant HCC cells. Using a panel of HCC cell lines and normal hepatocellular cells as control, we showed that cobimetinib is active against HCC cells and spare normal hepatocellular cells. Cobimetinib at nanomolar concentration inhibited proliferation and induced apoptosis in sorafenib-resistant HCC cells (Hep3B-r), suggesting its ability to overcome HCC resistance to standard of care. This was further demonstrated by our results that cobimetinib significantly augmented the inhibitory effects of sorafenib and doxorubicin in HCC cells. Notably, cobimetinib dose-dependently inhibited tumor angiogenesis by inhibiting HCC endothelial cell (HCCEC) growth, survival and capillary network work formation. Cobimetinib suppressed ERK/RSK without affecting JNK or p38 signaling pathways in Hep3B-r and HCCEC cells. In addition, cobimetinib negatively influenced the apoptosis pathways by increasing pro-apoptotic protein Bim and decreasing anti-apoptotic proteins Mcl-1 and Bcl-2. In addition, we validated the in vitro findings in HCC xenograft mouse model and demonstrated that cobimetinib inhibited ERK signaling, promoted apoptosis, and was active against resistant HCC growth and angiogenesis in vivo, without causing significant toxicity in mice. Our findings support the clinical trials of cobimetinib for HCC treatment and highlight the therapeutic value of inhibiting MEK/ERK/RSK to overcome HCC resistance.

Increasing costs, much time consumption and high risk of failure associated with the process of de novo development of new anticancer drugs have prompted the pharmaceutical industry to seek alternative strategies that may facilitate and accelerate the whole process. In particular, the repurposing strategy, known also as repositioning or reprofiling strategy, is a potential source of new treatment options for cancer patients with high unmet medical needs. However, it should be noted that the repurposing strategy, being still a new trend in drug development, should only complement the process of discovering new anticancer drugs, and should not be its alternative. The best repurposable oncological drug candidates are the agents whose original patent protection has already expired, and for which there is a possibility to create a formulation enabling, together with a new therapeutic indication, new patent protection. In this review article we discuss the advantages of the repurposing strategy, and provide an overview of a number of promising candidates, such as artesunate, aspirin, cimetidine, doxycycline, ivermectin, metformin, rapamycin (sirolimus), and thalidomide, that have the potential to be repurposed as anticancer drugs both in cancer prevention and therapy. In addition, we highlight some of the studies regarding the signalling pathways and molecular targets altered by these drugs, and describe the biological mechanisms underlying their anticancer effects.

Isoprenylcysteine carboxylmethyltransferase (Icmt) which catalyzes the final step of prenylation of many oncoproteins, such as Ras. Despite studies on Icmt and its regulation in biological activities of various cancers, little is known on the expression, function and mechanisms of the impact of Icmt on hepatocellular carcinoma (HCC). We report here the findings that Icmt is critical for HCC growth, migration, survival and chemoresistance by multiple oncogenic pathways. Expression analysis on primary patient and cell line samples demonstrated that Icmt protein level was significantly higher in the majority (∼70%) of HCC tissues and cells than corresponding normal counterparts. Icmt depletion inhibited growth, survival and migration in HCC cells, and augmented the inhibitory effects of doxorubicin. Consistently, Icmt also inhibited growth, and migration, and induced apoptosis in HCC cells that are resistant to doxorubicin. In contrast, Icmt overexpression promoted growth and migration in normal liver cells. Mechanistically, Icmt inhibition suppressed Ras/Raf/Mek/Erk signaling and epithelial-mesenchymal transition (EMT) in HCC cells. Several different approaches demonstrated that Icmt was critical for HCC biological activities with the predominant role in cell response to chemotherapy. This previously unappreciated function of Icmt can be targeted to enhance chemotherapy in particular those HCC patients with high Icmt expression.

Better understanding of the molecular mechanism involved in hepatocellular carcinoma (HCC) progression is essential for the development of therapeutic strategies to overcome chemoresistance in HCC patients. In this work, we show that 6-phosphogluconate dehydrogenase (6PGD), a key enzyme of the oxidative pentose phosphate pathway, is important for HCC growth and survival. Compared to normal liver tissues, we demonstrate that 6PGD expression is upregulated in HCC tissues. 6PGD overexpression increases 6PGD activity and promotes growth in normal liver cells. In contrast, targeting 6PGD using both genetic and pharmacological approaches inhibits HCC growth and survival. Combination of chemotherapeutic agents with 6PGD inhibition achieves greater efficacy in inhibiting HCC growth and survival than chemotherapeutic agent alone. We further show that inhibition of 6PGD activates AMP-activated protein kinase (AMPK) and acetyl-coenzyme A carboxylase 1 (ACC1), and decreases level of NADPH/NAD + and NADH in HCC, leading to SIRT1 activity reduction and oxidative stress. Conversely, AMPK depletion significantly abolishes the effects of physcion (a selective small-molecule 6PGD inhibitor) in decreasing NADPH/NAD + ratio, growth and survival, confirming the role of AMPK as the relevant upstream activator with 6PGD inhibition in HCC cells. Our work is the first to demonstrate the upregulation of 6PGD and its critical involvement in growth and survival in HCC. Our findings suggest 6PGD as a promising therapeutic target to overcome chemoresistance in HCC.

Nearly 37 million people were living worldwide with human immunodeficiency virus (HIV) infection in 2016, and about 2 million become infected every year. Acquired immunodeficiency syndrome (AIDS) is defined as HIV infection associated with an absolute CD4 count below 200/uL (age 6 and older) and/or an AIDS-defining opportunistic infection or AIDS-defined cancer, including Kaposi sarcoma (KS), non-Hodgkin lymphoma, and cervical cancer. About 40% of HIV-associated malignancies are associated with oncogenic viruses, including human papillomavirus (HPV), Epstein-Barr virus (EBV), human herpesvirus 8(HHV-8), and hepatitis B and C viruses.

KS is an angioproliferative tumor that originates when HHV-8 infects cells of endothelial lineage and maintains replication during host cell division. The use of combination antiretroviral therapy is a cornerstone of therapy for patients with HIV-associated KS. Other key considerations in the management of KS include the location, extent, and type of skin lesions, and immune function.

HIV infection itself appears not directly involved in carcinogenesis but results in disrupted immune surveillance of tumor antigens and oncogenic viruses. It also provides a milieu of chronic antigen stimulation, cytokine dysregulation, and genetic alterations, which is permissive for lymphomagenesis. EBV and HHV-8 are involved in lymphoma pathogenesis.

The most common anogenital cancers in HIV-infected individuals include squamous cell carcinoma of the cervix (women) and anal canal (men and women). Both are almost always associated with HPV infection, are potentially curable when disease is localized, may be detected at precancerous stages and possibly prevented with local therapy, and potentially could be prevented with HPV vaccination.