A Historical Tale of Two Lymphomas: Part II: Non-Hodgkin lymphoma

Lakhtakia, Ritu; Burney, Ikram A.

doi:10.18295/squmj.2015.15.03.003

Cited by 19 publications

(15 citation statements)

References 59 publications

(36 reference statements)

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“…R-CHOP has five constituents: R – rituximab, a humanized monoclonal antibody against CD20, a protein expressed on the surface of all B cells; C – cyclophosphamide (Cytoxan) an alkylating agent; H – hydroxydaunomycin (doxorubicin, or Adriamycin), a topoisomerase II inhibitor; O – Oncovin (vincristine), an anti-microtubule drug and; P – prednisone, a steroid. R-CHOP was developed over an extended period of time via clinical experiments in humans (Lakhtakia and Burney, 2015). The constituents of R-CHOP are known to be individually cytotoxic to DLBCL cells in vivo, and the drugs have largely non-overlapping dose-limiting toxicities, which permits their combined administration in patients.…”

Section: Introductionmentioning

confidence: 99%

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

Palmer

Chidley

Sorger

2019

eLife

102

101

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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 model 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.

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Section: Introductionmentioning

confidence: 99%

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

Palmer

Chidley

Sorger

2019

eLife

102

101

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“…For example, a combination of ethambutol, isoniazid and rifampicin (EIR), drugs with distinct mechanisms of action, is the standard treatment against M. tuberculosis (Mtb) 2 . Similarly, the standard treatment against Diffuse Large B-Cell Lymphoma is a combination of five drugs (R-CHOP) with different targets 3 . A treatment with many distinct drugs impose multiple bottlenecks for resistance evolution in heterogeneous cell populations 4,5 .…”

Section: Introductionmentioning

confidence: 99%

Design of high-order antibiotic combinations against M. tuberculosis by ranking and exclusion

Yılancıoğlu

Çokol

2019

Sci Rep

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combinations of more than two drugs are routinely used for the treatment of pathogens and tumors. High-order combinations may be chosen due to their non-overlapping resistance mechanisms or for favorable drug interactions. Synergistic/antagonistic interactions occur when the combination has a higher/lower effect than the sum of individual drug effects. The standard treatment of Mycobacterium tuberculosis (Mtb) is an additive cocktail of three drugs which have different targets. Herein, we experimentally measured all 190 pairwise interactions among 20 antibiotics against Mtb growth. We used the pairwise interaction data to rank all possible high-order combinations by strength of synergy/ antagonism. We used drug interaction profile correlation as a proxy for drug similarity to establish exclusion criteria for ideal combination therapies. Using this ranking and exclusion design (R/eD) framework, we modeled ways to improve the standard 3-drug combination with the addition of new drugs. We applied this framework to find the best 4-drug combinations against drug-resistant Mtb by adding new exclusion criteria to R/ED. Finally, we modeled alternating 2-order combinations as a cycling treatment and found optimized regimens significantly reduced the overall effective dose. R/ED provides an adaptable framework for the design of high-order drug combinations against any pathogen or tumor. Combinations of three or more drugs are frequently used in the treatment of pathogens and tumors. Such high-order combinations are generally constructed by combining drugs that are effective and with non-overlapping resistance mechanisms 1. For example, a combination of ethambutol, isoniazid and rifampicin (EIR), drugs with distinct mechanisms of action, is the standard treatment against M. tuberculosis (Mtb) 2. Similarly, the standard treatment against Diffuse Large B-Cell Lymphoma is a combination of five drugs (R-CHOP) with different targets 3. A treatment with many distinct drugs impose multiple bottlenecks for resistance evolution in heterogeneous cell populations 4,5. This 50-year-old hypothesis has been the main design element for high-order drug combinations and has been recently supported by empirical evidence 1. Combinations of drugs may interact, that is, the combination's effect may be significantly different than the sum of individual effects 6. If the combination's effect is more, equal or less than the sum of individual effects, the combination has synergistic, additive or antagonistic interaction, respectively 7,8. Synergistic combinations allow for dose-reduction thereby alleviating high-toxicity, or dose-escalation for restricting resistance evolution 9,10. Despite the high potential of high-order synergistic combinations for treatment improvement, a very large portion of studies focus on combinations of only two drugs. The number of possible ways to combine a set of n drugs is 2 n , there are only (n choose 2) combinations with two drugs. For example, there are 1,048,576 mathematically possible combinations among 20 drugs...

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“…The history of lymphomas can be traced back to the 17th century with a report from 1666 (Lakhtakia & Burney, ), although it took until the 19th century for Thomas Hodgkin to publish his now famous paper on “Some morbid appearance of the absorbent glands and spleen”, where he detailed historical clinical findings of a similar disease together with his own cases (Hodgkin, ). Since then, various sub‐types of lymphoma have been characterised.…”

Section: The History Of Alclmentioning

confidence: 99%

“…Due to the increasing complexity of these malignancies there have been a number of attempts to standardise classification of lymphomas. Anaplastic Large Cell Lymphoma (ALCL) was only established as a distinct clinical entity in 2001 with the publication of the World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues (Bonadonna, ; Jaffe et al , ; Lakhtakia & Burney, ).…”

Section: The History Of Alclmentioning

confidence: 99%

From bench to bedside: the past, present and future of therapy for systemic paediatric ALCL, ALK+

et al. 2019

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Anaplastic large cell lymphoma (ALCL) is a T cell Non-Hodgkin Lymphoma that mainly presents in paediatric and young adult patients. The majority of cases express a chimeric fusion protein resulting in hyperactivation of anaplastic lymphoma kinase (ALK) as the consequence of a chromosomal translocation. Rarer cases lack expression of ALK fusion proteins and are categorised as ALCL, ALKÀ. An adapted regimen of an historic chemotherapy backbone is still used to this day, yielding overall survival (OS) of over 90% but with event-free survival (EFS) at an unacceptable 70%, improving little over the past 30 years. It is clear that continued adaption of current therapies will probably not improve these statistics and, for progress to be made, integration of biology with the design and implementation of future clinical trials is required. Indeed, advances in our understanding of the biology of ALCL are outstripping our ability to clinically translate them; laboratory-based research has highlighted a plethora of potential therapeutic targets but, with high survival rates combined with a scarcity of funding and patients to implement paediatric trials of novel agents, progress is slow. However, advances must be made to reduce the side-effects of intensive chemotherapy regimens whilst maintaining, if not improving, OS and EFS.

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A Historical Tale of Two Lymphomas: Part II: Non-Hodgkin lymphoma

Cited by 19 publications

References 59 publications

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

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

Design of high-order antibiotic combinations against M. tuberculosis by ranking and exclusion

From bench to bedside: the past, present and future of therapy for systemic paediatric ALCL, ALK+

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