Beyond PARP1: The Potential of Other Members of the Poly (ADP-Ribose) Polymerase Family in DNA Repair and Cancer Therapeutics

The proteins within the Poly-ADP Ribose Polymerase (PARP) family encompass a diverse and integral set of cellular functions. PARP1 and PARP2 have been extensively studied for their roles in DNA repair and as targets for cancer therapeutics. Several PARP inhibitors (PARPi) have been approved for clinical use, however, while their efficacy is promising, tumours readily develop PARPi resistance. Many other members of the PARP protein family share catalytic domain homology with PARP1/2, however, these proteins are comparatively understudied, particularly in the context of DNA damage repair and tumourigenesis. This review explores the functions of PARP4,6-16 and discusses the current knowledge of the potential roles these proteins may play in DNA damage repair and as targets for cancer therapeutics.

Targeted Delivery of Exosomes Armed with Anti-Cancer Therapeutics

Among extracellular vesicles, exosomes have gained great attention for their role as therapeutic vehicles for delivering various active pharmaceutical ingredients (APIs). Exosomes “armed” with anti-cancer therapeutics possess great potential for an efficient intracellular delivery of anti-cancer APIs and enhanced targetability to tumor cells. Various technologies are being developed to efficiently incorporate anti-cancer APIs such as genetic materials (miRNA, siRNA, mRNA), chemotherapeutics, and proteins into exosomes and to induce targeted delivery to tumor burden by exosomal surface modification. Exosomes can incorporate the desired therapeutic molecules via direct exogenous methods (e.g., electroporation and sonication) or indirect methods by modifying cells to produce “armed” exosomes. The targeted delivery of “armed” exosomes to tumor burden could be accomplished either by “passive” targeting using the natural tropism of exosomes or by “active” targeting via the surface engineering of exosomal membranes. Although anti-cancer exosome therapeutics demonstrated promising results in preclinical studies, success in clinical trials requires thorough validation in terms of chemistry, manufacturing, and control techniques. While exosomes possess multiple advantages over synthetic nanoparticles, challenges remain in increasing the loading efficiency of anti-cancer agents into exosomes, as well as establishing quantitative and qualitative analytical methods for monitoring the delivery of in vivo administered exosomes and exosome-incorporated anti-cancer agents to the tumor parenchyma.

Tackling the Behavior of Cancer Cells: Molecular Bases for Repurposing Antipsychotic Drugs in the Treatment of Glioblastoma

Glioblastoma (GBM) is associated with a very dismal prognosis, and current therapeutic options still retain an overall unsatisfactorily efficacy in clinical practice. Therefore, novel therapeutic approaches and effective medications are highly needed. Since the development of new drugs is an extremely long, complex and expensive process, researchers and clinicians are increasingly considering drug repositioning/repurposing as a valid alternative to the standard research process. Drug repurposing is also under active investigation in GBM therapy, since a wide range of noncancer and cancer therapeutics have been proposed or investigated in clinical trials. Among these, a remarkable role is played by the antipsychotic drugs, thanks to some still partially unexplored, interesting features of these agents. Indeed, antipsychotic drugs have been described to interfere at variable incisiveness with most hallmarks of cancer. In this review, we analyze the effects of antipsychotics in oncology and how these drugs can interfere with the hallmarks of cancer in GBM. Overall, according to available evidence, mostly at the preclinical level, it is possible to speculate that repurposing of antipsychotics in GBM therapy might contribute to providing potentially effective and inexpensive therapies for patients with this disease.

In Silico Design, Synthesis, and Biological Evaluation of Anticancer Arylsulfonamide Endowed with Anti-Telomerase Activity

Telomerase, a reverse transcriptase enzyme involved in DNA synthesis, has a tangible role in tumor progression. Several studies have evidenced telomerase as a promising target for developing cancer therapeutics. The main reason is due to the overexpression of telomerase in cancer cells (85–90%) compared with normal cells where it is almost unexpressed. In this paper, we used a structure-based approach to design potential inhibitors of the telomerase active site. The MYSHAPE (Molecular dYnamics SHared PharmacophorE) approach and docking were used to screen an in-house library of 126 arylsulfonamide derivatives. Promising compounds were synthesized using classical and green methods. Compound 2C revealed an interesting IC50 (33 ± 4 µM) against the K-562 cell line compared with the known telomerase inhibitor BIBR1532 IC50 (208 ± 11 µM) with an SI ~10 compared to the BALB/3-T3 cell line. A 100 ns MD simulation of 2C in the telomerase active site evidenced Phe494 as the key residue as well as in BIBR1532. Each moiety of compound 2C was involved in key interactions with some residues of the active site: Arg557, Ile550, and Gly553. Compound 2C, as an arylsulfonamide derivative, is an interesting hit compound that deserves further investigation in terms of optimization of its structure to obtain more active telomerase inhibitors

EZH2 depletion potentiates MYC degradation inhibiting neuroblastoma and small cell carcinoma tumor formation

Efforts to therapeutically target EZH2 have generally focused on inhibition of its methyltransferase activity, although it remains less clear whether this is the central mechanism whereby EZH2 promotes cancer. In the current study, we show that EZH2 directly interacts with both MYC family oncoproteins, MYC and MYCN, and promotes their stabilization in a methyltransferase-independent manner. By competing against the SCFFBW7 ubiquitin ligase to bind MYC and MYCN, EZH2 counteracts FBW7-mediated MYC(N) polyubiquitination and proteasomal degradation. Depletion, but not enzymatic inhibition, of EZH2 induces robust MYC(N) degradation and inhibits tumor cell growth in MYC(N) driven neuroblastoma and small cell lung carcinoma. Here, we demonstrate the MYC family proteins as global EZH2 oncogenic effectors and EZH2 pharmacologic degraders as potential MYC(N) targeted cancer therapeutics, pointing out that MYC(N) driven cancers may develop inherent resistance to the canonical EZH2 enzymatic inhibitors currently in clinical development.

Validation of a combined ultrasound and bioluminescence imaging system with magnetic resonance imaging in orthotopic pancreatic murine tumors

Preclinical mouse solid tumor models are widely used to evaluate efficacy of novel cancer therapeutics. Recent reports have highlighted the need for utilizing orthotopic implantation to represent clinical disease more accurately, however the deep tissue location of these tumors makes longitudinal assessment challenging without the use of imaging techniques. The purpose of this study was to evaluate the performance of a new multi-modality high-throughput in vivo imaging system that combines bioluminescence imaging (BLI) with robotic, hands-free ultrasound (US) for evaluating orthotopic mouse models. Long utilized in cancer research as independent modalities, we hypothesized that the combination of BLI and US would offer complementary advantages of detection sensitivity and quantification accuracy, while mitigating individual technological weaknesses. Bioluminescent pancreatic tumor cells were injected into the pancreas tail of C57BL/6 mice and imaged weekly with the combination system and magnetic resonance imaging (MRI) to serve as a gold standard. BLI photon flux was quantified to assess tumor activity and distribution, and US and MRI datasets were manually segmented for gross tumor volume. Robotic US and MRI demonstrated a strong agreement (R2 = 0.94) for tumor volume measurement. BLI showed a weak overall agreement with MRI (R2 = 0.21), however, it offered the greatest sensitivity to detecting the presence of tumors. We conclude that combining BLI with robotic US offers an efficient screening tool for orthotopic tumor models.

Engineering Nanoplatform for Combined Cancer Therapeutics via Complementary Autophagy Inhibition

Despite advances in the development of tumor treatments, mortality from cancer continues to increase. Nanotechnology is expected to provide an innovative anti-cancer therapy, to combat challenges such as multidrug resistance and tumor recurrence. Nevertheless, tumors can greatly rely on autophagy as an alternative source for metabolites, and which desensitizes cancer cells to therapeutic stress, hindering the success of any current treatment paradigm. Autophagy is a conserved process by which cells turn over their own constituents to maintain cellular homeostasis. The multistep autophagic pathway provides potentially druggable targets to inhibit pro-survival autophagy under various therapeutic stimuli. In this review, we focus on autophagy inhibition based on functional nanoplatforms, which may be a potential strategy to increase therapeutic sensitivity in combinational cancer therapies, including chemotherapy, radiotherapy, phototherapy, sonodynamic therapy, and immunotherapy.