A curative combination cancer therapy achieves high fractional cell killing through low cross-resistance and drug additivity

Curative cancer therapies are uncommon and nearly always involve multi-drug combinations developed by experimentation in humans; unfortunately, the mechanistic basis for the success of such combinations has rarely been investigated in detail, obscuring lessons learned. Here we use isobologram analysis to score pharmacological interaction, and clone tracing and CRISPR screening to measure cross-resistance among the five drugs comprising R ‑CHOP, a combination therapy that frequently cures Diffuse Large B-Cell Lymphomas. We find that drugs in R‑CHOP exhibit very low cross-resistance but not synergistic interaction: together they achieve a greater fractional kill according to the null hypothesis for both the Loewe dose-additivity m odel and the Bliss effect-independence model. These data provide direct evidence for the 50-year old hypothesis that a curative cancer therapy can be constructed on the basis of independently effective drugs having non-overlapping mechanisms of resistance, without synergistic interaction, which has immediate significance for the design of new drug combinations.
Source: eLife - Category: Biomedical Science Tags: Cancer Biology Computational and Systems Biology Source Type: research

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Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
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Source: Fight Aging! - Category: Research Authors: Tags: Medicine, Biotech, Research Source Type: blogs
nski J, Urbano-Ispizua A, Hayden PJ, Kröger N Abstract Chimeric antigen receptor T-cells are a novel class of anti-cancer therapy in which autologous or allogeneic T-cells are engineered to express a chimeric antigen receptor targeting a membrane antigen. In Europe, Tisagenlecleucel (KymriahTM) is approved for the treatment of refractory/relapsed Acute Lymphoblastic Leukaemia in children and young adults as well as relapsed/refractory Diffuse Large B-cell Lymphoma; Axicabtagene ciloleucel (YescartaTM) is approved for the treatment of relapsed/refractory high-grade B-cell Lymphoma and Primary Mediastinal B-cel...
Source: Haematologica - Category: Hematology Authors: Tags: Haematologica Source Type: research
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Source: Cancers - Category: Cancer & Oncology Authors: Tags: Review Source Type: research
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Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
Yicheng Ni Cancer remains a major cause of death globally. Given its relapsing and fatal features, curing cancer seems to be something hardly possible for the majority of patients. In view of the development in cancer therapies, this article summarizes currently available cancer therapeutics and cure potential by cancer type and stage at diagnosis, based on literature and database reviews. Currently common cancer therapeutics include surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy. However, treatment with curative intent by these methods are mainly eligible for patients with localized diseas...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Review Source Type: research
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Source: Current Pharmaceutical Design - Category: Drugs & Pharmacology Authors: Tags: Curr Pharm Des Source Type: research
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Source: Current Opinion in Infectious Diseases - Category: Infectious Diseases Tags: ANTIMICROBIAL AGENTS: BACTERIAL/FUNGAL: Edited by Monica Slavin Source Type: research
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Source: Biomed Res - Category: Research Authors: Tags: Biomed Res Int Source Type: research
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Source: The Oncologist - Category: Cancer & Oncology Authors: Tags: Oncologist Source Type: research
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