A Small Molecule–Drug Conjugate (SMDC) Consisting of a Modified Camptothecin Payload Linked to an αVß3 Binder for the Treatment of Multiple Cancer Types

To improve tumor selectivity of cytotoxic agents, we designed VIP236, a small molecule–drug conjugate consisting of an αVβ3 integrin binder linked to a modified camptothecin payload (VIP126), which is released by the enzyme neutrophil elastase (NE) in the tumor microenvironment (TME). The tumor targeting and pharmacokinetics of VIP236 were studied in tumor-bearing mice by in vivo near-infrared imaging and by analyzing tumor and plasma samples. The efficacy of VIP236 was investigated in a panel of cancer cell lines in vitro, and in MX-1, NCI-H69, and SW480 murine xenograft models. Imaging studies with the αVβ3 binder demonstrated efficient tumor targeting. Administration of VIP126 via VIP236 resulted in a 10-fold improvement in the tumor/plasma ratio of VIP126 compared with VIP126 administered alone. Unlike SN38, VIP126 is not a substrate of P-gp and BCRP drug transporters. VIP236 presented strong cytotoxic activity in the presence of NE. VIP236 treatment resulted in tumor regressions and very good tolerability in all in vivo models tested. VIP236 represents a novel approach for delivering a potent cytotoxic agent by utilizing αVβ3 as a targeting moiety and NE in the TME to release the VIP126 payload—designed for high permeability and low efflux—directly into the tumor stroma.

Secondary Metabolites from Marine-Derived Fungi and Actinobacteria as Potential Sources of Novel Colorectal Cancer Drugs

Colorectal cancer is one of the most common cancers diagnosed in the world. Chemotheraphy is one of the most common methods used for the pharmacological treatment of this cancer patients. Nevertheless, the adverse effect of chemotherapy is not optimized for improving the quality of life of people who are older, who are the most vulnerable subpopulation. This review presents recent updates regarding secondary metabolites derived from marine fungi and actinobacteria as novel alternatives for cytotoxic agents against colorectal cancer cell lines HCT116, HT29, HCT15, RKO, Caco-2, and SW480. The observed marine-derived fungi were from the species Aspergillus sp., Penicillium sp., Neosartorya sp., Dichotomomyces sp., Paradendryphiella sp., and Westerdykella sp. Additionally, Streptomyces sp. and Nocardiopsis sp. are actinobacteria discussed in this study. Seventy one compounds reviewed in this study were grouped on the basis of their chemical structures. Indole alkaloids and diketopiperazines made up most compounds with higher potencies when compared with other groups. The potency of indole alkaloids and diketopiperazines was most probably due to halogen-based functional groups and sulfide groups, respectively.

Accumulation of Cytochrome b558 at the Plasma Membrane: Hallmark of Oxidative Stress in Phagocytic Cells

Neutrophils play a very key role in the human immune defense against pathogenic infections. The predominant players in this role during the activation of neutrophils are the release of cytotoxic agents stored in the granules and secretory vesicles and the massive production of reactive oxygen species (ROS) initiated by the enzyme NADPH oxidase. In addition, in living organisms, cells are continuously exposed to endogenous (inflammations, elevated neutrophil presence in the vicinity) and exogenous ROS at low and moderate levels (travels by plane, radiotherapy, space irradiation, blood banking, etc.). To study these effects, we used ROS induced by gamma radiation from low (0.2 Gy) to high (25 Gy) dose levels on PLB-985 cells from a myeloid cell line differentiated to neutrophil-like cells that are considered a good alternative to neutrophils. We determined a much longer lifetime of PLB-985 cells than that of neutrophils, which, as expected, decreased by increasing the irradiation dose. In the absence of any secondary stimulus, a very low production of ROS is detected with no significant difference between irradiated and non-irradiated cells. However, in phagocytosing cells, irradiation doses above 2 Gy enhanced oxidative burst in PLB-985 cells. Whatever the irradiation dose, NADPH oxidase devoid of its cytosolic regulatory units is observed at the plasma membrane in irradiated PLB-985 cells. This result is different from that observed for irradiated neutrophils in which irradiation also induced a translocation of regulatory subunits suggesting that the signal transduction mechanism or pathway operate differently in both cells.

Oxaliplatin-Induced Peripheral Neuropathy Can Be Minimized By Pressurized Regional Intravascular Delivery In An Orthotopic Murine Pancreatic Cancer Model.

Purpose: There is a great need to reduce the toxicity of chemotherapy used in the management of pancreatic ductal adenocarcinoma (PDAC). Here we explore if regional pressurized delivery of oxaliplatin can minimize peripheral neuropathy in mice.Methods: We used an orthotopic PDAC mouse model and delivered a single dose of oxaliplatin through the portal vein using a pressure-enabled system (pancreatic retrograde venous infusion, PRVI). We analyzed the effects of PRVI on tumor burden and peripheral neuropathy using histopathological and functional assays.Results: Tumor weights in mice treated with 2 mg/Kg oxaliplatin using PRVI were significantly lower than in mice treated with the same dose systemically. This resulted in reduced peripheral neuropathy signatures in PRVI mice compared to the 20 mg/Kg systemic dose required to achieve similar tumor control.Conclusion: Regional delivery of highly cytotoxic agents using PRVI can reduce the therapeutic dose of these drugs, thereby lowering toxic side effects.

Prospects in the management of patients with follicular lymphoma beyond first-line therapy

The management of patients with relapsed or refractory follicular lymphoma has evolved markedly in the last decade, with the availability of new classes of agents (phosphoinositide 3-kinase inhibitors, immunomodulators, epigenetic therapies, and chimeric antigen receptor T cells) supplementing the multiple approaches already available (cytotoxic agents, anti-CD20 antibodies, radiation therapy, radioimmunotherapy, and autologous and allogeneic transplants). The diversity of clinical scenarios, the flood of data derived from phase II studies, and the lack of randomized studies comparing treatment strategies preclude firm recommendations and require personalized decisions. Patients with early progression require specific attention given the risk of histological transformation and their lower response to standard therapies. In sequencing therapies, one must consider prior treatment regimens and the potential need for future lines of therapy. Careful evaluation of risks and expected benefits of available options, which vary depending on location and socioeconomics, should be undertaken, and should incorporate the patient’s goals. Preserving quality of life for these patients is essential, given the likelihood of years to decades of survival and the possibility of multiple lines of therapy. The current landscape is likely to continue evolving rapidly with other effective agents emerging (notably bispecific antibodies and other targeted therapies), and multiple combinations being evaluated. It is hoped that new treatments under development will achieve longer progression-free intervals and minimize toxicity. A better understanding of disease biology and the mechanisms of these different agents should provide further insights to select the optimal therapy at each stage of disease.

Novel ADCs and Strategies to Overcome Resistance to Anti-HER2 ADCs

During recent years, a number of new compounds against HER2 have reached clinics, improving the prognosis and quality of life of HER2-positive breast cancer patients. Nonetheless, resistance to standard-of-care drugs has motivated the development of novel agents, such as new antibody-drug conjugates (ADCs). The latter are a group of drugs that benefit from the potency of cytotoxic agents whose action is specifically guided to the tumor by the target-specific antibody. Two anti-HER2 ADCs have reached the clinic: trastuzumab-emtansine and, more recently, trastuzumab-deruxtecan. In addition, several other HER2-targeted ADCs are in preclinical or clinical development, some of them with promising signs of activity. In the present review, the structure, mechanism of action, and potential resistance to all these ADCs will be described. Specific attention will be given to discussing novel strategies to circumvent resistance to ADCs.

Rational drug combinations with CDK4/6 inhibitors in acute lymphoblastic Leukemia

Despite improvements in outcomes for children with B and T-cell acute lymphoblastic leukemia (B-ALL and T-ALL), patients with resistant or relapsed disease fare poorly. Previous studies have demonstrated the essential role of cyclin D3 in T-ALL disease initiation and progression and that targeting of the CDK4/6-cyclin D complex can suppress T-ALL proliferation, leading to efficient cell death in animal models. Studies in leukemia and other malignancies, suggest that schedule is important when combining CDK4/6 inhibitors (CDKis) with cytotoxic agents. Based on these observations, we broadened evaluation of two CDKis, palbociclib (PD-0332991, Pfizer) and ribociclib (LEE011, Novartis) in B and T-ALL as single agent and in combination with conventional cytotoxic chemotherapy, using different schedules in preclinical models. As monotherapy, CDKis caused cell cycle arrest with a significant decrease in S phase entry and were active in vivo across a broad number of patient-derived xenograft samples. Prolonged monotherapy induces resistance, for which we identified a potential novel mechanism using transcriptome profiling. Importantly, simultaneous but not sequential treatment of CDKis with conventional chemotherapy (dexamethasone, L-asparaginase and vincristine) led to improved efficacy compared to monotherapy in vivo. We provide novel evidence that combining CDKis and conventional chemotherapy can be safe and effective. These results led to the rational design of a clinical trial.

Tracing and Targeting the Origins of Childhood Cancer

Despite the success of treating childhood cancers with cytotoxic agents, novel therapeutic strategies are required to achieve the next leap in cure rates. A promising avenue may be to target the origin of childhood cancers. Here, we review recent advances in tracing the origins of pediatric tumors. Cancer-to-normal cell comparisons by single-cell mRNA sequencing reveal the fetal state of cancer cells, as well as their cell of origin. Recent phylogenetic analyses have uncovered large tissue-resident precursor clones to childhood cancers, which already possess key genomic alterations leading to tumor formation. Both the transcriptional fetalness and genomic status of the premalignant tissue bed provide further avenues for targeted therapy. Overall, these advances begin to describe the precise origins of pediatric tumors and pave the way for novel methods in detecting, treating, and perhaps even preventing childhood cancers. Expected final online publication date for the Annual Review of Cancer Biology, Volume 6 is April 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Synthesis and Evaluation of bis-Schiff Bases of Carbohydrazide as Antioxidant and Cytotoxic Agents

Background & Introduction : Antioxidants are known to prevent oxidative stress-induced damage to the biomolecules and thus, delay the onset of cancers and many age-related diseases. Therefore, the development of novel and potent antioxidants is justified. Method: During this study, we synthesized symmetrical bis-Schiff bases of carbohydrazide 1-27, and evaluated their in vitro antioxidative activity and cytotoxic activity. Results: Among synthesized compounds, six compounds 20 (IC50 = 12.89 ± 0.02 µM), 16 (IC50 = 14.32 ± 0.43 µM), 17 (IC50 = 18.52 ± 0.83 µM), 19 (IC50 = 22.84 ± 0.62 µM), 24 (IC50 = 35.1 ± 0.82 µM) and 15 (IC50 = 40.03 ± 1.06 µM) showed an excellent 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, better than the standard butylatedhydroxyanisole (BHA) (IC50 = 44.6 ± 0.6 µM). Likewise, two compounds 16 (IC50 = 4.3 ± 1.3 µM) and 20 (IC50 = 6.6 ± 1.6 µM) showed oxidative burst scavenging activity better than the standard drug ibuprofen (IC50 = 11.2 ± 1.9 µM). Some synthesized compounds showed good to moderate toxicity against prostate cancer (PC-3) cell lines. Conclusion: This study has identified potent antioxidants and good cytotoxic agents with the potential to further investigate.