Genotype-based chemotherapy for patients with gastrointestinal tumors: focus on oxaliplatin, irinotecan, and fluoropyrimidines

This review aimed to summarize the pharmacogenetic studies of the most commonly used drugs in the chemotherapy of gastrointestinal (GI) tumors: oxaliplatin, irinotecan, and fluoropyrimidines. So far, it has not been possible to develop an effective genotype-based approach for oxaliplatin. More and more evidence is emerging in favor of the fact that the choice of a dose of fluorouracil based on pharmacogenetic testing according to DPYD*2A, can be not only effective but also cost-effective. Additional, well-planned trials of the UGT1A1 genotype-based approach to irinotecan therapy are predicted to reduce adverse drug events in people with the UGT1A1*28/*28 genotypes and improve treatment efficacy in the rest of the patients, which might be cost-effective.

Pharmacologically controlling protein-protein interactions through epichaperomes for therapeutic vulnerability in cancer

Cancer cell plasticity due to the dynamic architecture of interactome networks provides a vexing outlet for therapy evasion. Here, through chemical biology approaches for systems level exploration of protein connectivity changes applied to pancreatic cancer cell lines, patient biospecimens, and cell- and patient-derived xenografts in mice, we demonstrate interactomes can be re-engineered for vulnerability. By manipulating epichaperomes pharmacologically, we control and anticipate how thousands of proteins interact in real-time within tumours. Further, we can essentially force tumours into interactome hyperconnectivity and maximal protein-protein interaction capacity, a state whereby no rebound pathways can be deployed and where alternative signalling is supressed. This approach therefore primes interactomes to enhance vulnerability and improve treatment efficacy, enabling therapeutics with traditionally poor performance to become highly efficacious. These findings provide proof-of-principle for a paradigm to overcome drug resistance through pharmacologic manipulation of proteome-wide protein-protein interaction networks.

Injectable Nanoparticle-Based Hydrogels Enable the Safe and Effective Deployment of Immunostimulatory CD40 Agonist Antibodies

When properly deployed, the immune system can render deadly pathogens harmless, eradicate metastatic cancers, and provide long-lasting protection from diverse diseases. However, realizing these remarkable capabilities is inherently risky, as disruption to immune homeostasis can lead to dangerous complications and autoimmune disorders. While current research is continuously expanding the arsenal of potent immunotherapeutics, there is a technological gap when it comes to controlling when, where, and how long these drugs act on the body. Here, we explored the ability of a slow-releasing injectable hydrogel depot to reduce the problematic dose-limiting toxicities of immunostimulatory CD40 agonist antibodies (CD40a) while maintaining their potent anti-cancer efficacy. We previously described a polymer-nanoparticle (PNP) hydrogel system that is biocompatible, long lasting, and injectable, traits that we hypothesized would improve locoregional delivery of the CD40a immunotherapy. Using PET imaging, we found that hydrogels significantly improve CD40a pharmacokinetics by redistributing drug exposure to the tumor and the tumor draining lymph node (TdLN). Consistent with this altered biodistribution, hydrogel delivery significantly reduced weight loss, hepatotoxicity, and cytokine storm associated with treatment. Moreover, CD40a-loaded hydrogels were able to mediate improved local cytokine induction in the TdLN and improve treatment efficacy in both mono- and combination therapy settings in the B16F10 melanoma model. These results suggest that PNP hydrogels are a facile, drug-agnostic method to ameliorate immune-related adverse effects and explore locoregional delivery of immunostimulatory drugs.

Immunotherapy Combined With Radiation Therapy for Genitourinary Malignancies

Immunotherapy drugs have recently been approved by the Food and Drug Administration for the treatment of several genitourinary malignancies, including bladder cancer, renal cancer, and prostate cancer. Preclinical data and early clinical trial results suggest that immune checkpoint inhibitors can act synergistically with radiation therapy to enhance tumor cell killing at local irradiated sites and in some cases at distant sites through an abscopal effect. Because radiation therapy is commonly used in the treatment of genitourinary malignancies, there is great interest in testing the combination of immunotherapy with radiation therapy in these cancers to further improve treatment efficacy. In this review, we discuss the current evidence and biological rationale for combining immunotherapy with radiation therapy, as well as emerging data from ongoing and planned clinical trials testing the efficacy and tolerability of this combination in the treatment of genitourinary malignancies. We also outline outstanding questions regarding sequencing, dose fractionation, and biomarkers that remain to be addressed for the optimal delivery of this promising treatment approach.

Counterproductive effects of Daratumumab and checkpoint inhibitor for the treatment of patients with relapsing NK/T lymphoma

ABSTRACTNatural killer/T cell lymphoma (NK/T L) is an aggressive malignancy associated with poor prognosis in relapsed patients. Although L-asparaginase based treatments are recommended as first-line treatment in relapsed patients, advances in immunotherapies such as checkpoint inhibitions have provided new therapeutic alternatives. However, as clinical outcomes for checkpoint inhibitors seemed to vary between NK/T L patients, combination therapies have been suggested to improve treatment efficacy. Here, we compared the effects of Daratumumab (anti-CD38)/anti-PD-1 combination therapy versus anti-PD-1 monotherapy on two relapsed NK/T L patients. Anti-PD-1 triggered an upregulation of CD38 on activated T cells, leading to depletion by Daratumumab. Concomittantly, EBV-specific antibody titer was also reduced alongside with depletion of CD38+ B cells and antibody-producing plasmablasts. Taken together, combining anti-CD38 and anti-PD-1 is likely to be antithetic.

Chem-inspired hollow ceria nanozymes with lysosome-target for tumor synergistic phototherapy

The precise operation of the hypoxic tumor microenvironment presents a promising way to improve treatment efficacy, especially in tumor synergistic phototherapy. This work reports an innovative approach to build adenosine...

Mechanisms of Immunosuppression in Colorectal Cancer

CRC is the third most diagnosed cancer in the US with the second-highest mortality rate. A multi-modality approach with surgery/chemotherapy is used in patients with early stages of colon cancer. Radiation therapy is added to the armamentarium in patients with locally advanced rectal cancer. While some patients with metastatic CRC are cured, the majority remain incurable and receive palliative chemotherapy as the standard of care. Recently, immune checkpoint blockade has emerged as a promising treatment for many solid tumors, including CRC with microsatellite instability. However, it has not been effective for microsatellite stable CRC. Here, main mechanisms of immunosuppression in CRC will be discussed, aiming to provide some insights for restoring immunosurveillance to improve treatment efficacy in CRC.

Impact of Loading Dose of Caspofungin in Pharmacokinetic-Pharmacodynamic Target Attainment for Severe Candidiasis Infections in Patients in Intensive Care Units: the CASPOLOAD Study

ABSTRACT This study evaluated the impact of a high loading dose of caspofungin (CAS) on the pharmacokinetics of CAS and the pharmacokinetic-pharmacodynamic (PK-PD) target attainment in patients in intensive care units (ICU). ICU patients requiring CAS treatment were prospectively included to receive a 140-mg loading dose of CAS. Plasma CAS concentrations (0, 2, 3, 5, 7, and 24 h postinfusion) were determined to develop a two-compartmental population PK model. A Monte Carlo simulation was performed and the probabilities of target attainment (PTAs) were computed using previously published MICs. PK-PD targets were ratios of area under the concentration-time curve from 0 to 24 h (AUC0–24h) divided by the MIC (AUC0–24h/MIC) of 250, 450, and 865 and maximal concentration (Cmax) divided by the MIC (Cmax/MIC) of 5, 10, 15, and 20. Among 13 included patients, CAS clearance was 0.98 ± 0.13 liters/h and distribution volumes were V1 = 9.0 ± 1.2 liters and V2 = 11.9 ± 2.9 liters. Observed and simulated CAS AUC0–24h were 79.1 (IQR 55.2; 108.4) and 81.3 (IQR 63.8; 102.3) mg · h/liter during the first 24 h of therapy, which is comparable to values usually observed in ICU patients at day 3 or later. PTAs were >90% for MICs of 0.19 and 0.5 mg/liter, considering AUC/MIC = 250 and Cmax/MIC = 10 as PK-PD targets, respectively. Thus, a high loading dose of CAS (140 mg) increased CAS exposure in the first 24 h of therapy, allowing early achievement of PK-PD targets for most Candida strains. Such a strategy seems to improve treatment efficacy, though further studies are needed to assess the impact on clinical outcomes. (This study has been registered at ClinicalTrials.gov under identifier NCT02413892.)

Dual-target inhibitors based on BRD4: Novel therapeutic approaches for cancer

: Bromodomain and Extraterminal domain (BET) proteins are a family of important proteins to build transcriptionpromoting complexes by reading acetylated chromatin status and accumulating on transcriptionally active regulatory elements. BRD4 as an important member of BET family proteins can assist the expression of various well-known oncogenes, indicating that inhibiting BRD4 is an effective strategy for cancer treatment. In view of the fact that BRD4 inhibitor and inhibitors of some enzymatic/non-enzymatic proteins share many common targets and do similar effects on cellular processes, combined inhibition of BRD4 and these proteins is regarded as a rational strategy to improve treatment efficacy. In this review, we summarize the molecular interplay between BRD4 and other proteins. Moreover, we summarize the corresponding dual targeting inhibitors, for example HDAC/BRD4 dual inhibitors, PLK1/BRD4 dual inhibitors, PI3K/BRD4 dual inhibitors and so on, in cancer therapy and we make an insight into the structure-activity relationships of these dual-target agents.