The Effectiveness of Combinations of Antileukemic Agents in Inducing and Maintaining Remission in Children with Acute Leukemia

Frei, Emil; Karon, Myron; Levin, Robert H.; Freireich, Emil J.; Taylor, Robert J.; Hananian, Juliet; Selawry, Oleg S.; Holland, James F.; Hoogstraten, Barth; Wolman, Irving J.; Abir, Esshagh; Sawitsky, Arthur; Lee, S.; Mills, Stephen D.; Burgert, E. Omer; Spurr, Charles L.; Patterson, Richard B.; Ebaugh, Franklin G.; James, G. Watson; Moon, John H.

doi:10.1182/blood.v26.5.642.642

Cited by 279 publications

(99 citation statements)

References 7 publications

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“…Quantification of intratumoral genetic diversity and its relationship to therapy resistance began with the landmark 1965 use of combination therapy to prevent emergence of resistance in childhood leukemia 22 .…”

Section: Discussionmentioning

confidence: 99%

Unexpectedly High Subclonal Mutational Diversity in Human Colorectal Cancer and Its Significance

Loeb

Kohrn

Loubet-Senear

et al. 2019

Preprint

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Human colorectal cancers (CRC) contain both clonal and subclonal mutations. Clonal mutations are positively selected, present in most cells and drive malignant progression. Subclonal mutations are randomly dispersed throughout the genome; they provide a vast reservoir of mutant cells that can expand, repopulate the tumor and result in the rapid emergence of resistance, as well as being a major contributor to tumor heterogeneity. Here, we apply Duplex Sequencing (DS) methodology to quantify subclonal mutations in CRC tumor with unprecedented depth (10 4 ) and accuracy (<10 -7 ). We measured mutation frequencies in genes encoding replicative DNA polymerases and in genes frequently mutated in CRC, and found an unexpectedly high effective mutation rate, 7.1 X 10 -7 . The curve of subclonal mutation accumulation as a function of sequencing depth, using DNA obtained from five different tumors, is in accord with a neutral model of tumor evolution. We present a new theoretical approach to model neutral evolution independent of the infinite sites assumption (which states that a particular mutation arises only in one tumor cell at any given time). Our analysis indicates that the infinite sites assumption is not applicable once the number of tumor cells exceeds the reciprocal of the mutation rate, a circumstance relevant to even the smallest clinically diagnosable tumor. Our methods allow accurate estimation of the total mutation burden in clinical cancers. Our results indicate that no DNA locus is wild type in every malignant cell within a tumor at the time of diagnosis (probability of all cells wild type = 10 -308 ). Significance StatementCancers evolve many mutations. Clonal mutations are selected early. Subsequent evolution occurs in a branching fashion, possibly without selection ("neutral evolution"). Rarer mutations occur later on smaller branches of the evolutionary tree. Using a DNA sequencing method, duplex sequencing, with unprecedented accuracy and sensitivity, we quantified very rare unique subclonal mutations in diagnostic specimens from five human colorectal cancers. Rarer subclones probe later evolutionary timepoints than previously possible. We confirm neutral evolution at later times and find many more subclonal mutations than expected. A novel theoretical method allowed us to extrapolate further forward in time to diagnosis. At diagnosis, every base in DNA is mutated in at least one cancer cell. In particular any therapy resistance mutation would be present. Introduction:Accumulation of somatic mutations is a characteristic of cancer. Solid tumors contain numerous selected clonal mutations 1 . Subclonal mutations-each present in only a small fraction of malignant cells-also contribute to phenotypic and morphologic heterogeneity within a tumor 2 , and potentially to therapeutic resistance 3 . The extent of subclonal mutations in cancer has been difficult to quantify, as the high error rate of next-generation sequencing precludes reliable detection of mutations present in fewer than 5% of cells 4 .Here, we ...

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Section: Discussionmentioning

confidence: 99%

Unexpectedly High Subclonal Mutational Diversity in Human Colorectal Cancer and Its Significance

Loeb

Kohrn

Loubet-Senear

et al. 2019

Preprint

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“…Although the triumph of ABL inhibitors in enabling the long-term survival of patients with CML has been the model for targeted therapy in cancer, it is becoming clear that single-agent targeted therapy is unlikely to be curative in the majority of cancers. This is analogous to the paradigm of drug development in the 1960s for pediatric acute lymphoblastic leukemia, where empirical clinical trials over 30 years led to the advancement of a three-year combination chemotherapy regimen with five-year survival approaching 90% (39). This initial strategy was meant to be toxic to all leukemia cells before a subset have a chance to develop resistance to one agent.…”

Section: Understanding Mechanisms Of Drug Resistance Combination Versmentioning

confidence: 98%

Translating Genomics for Precision Cancer Medicine

Roychowdhury

Chinnaiyan²

2014

Annu. Rev. Genom. Hum. Genet.

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The Human Genome Project not only provided the essential reference map for the human genome but also stimulated the development of technology and analytic tools to process massive quantities of genomic data. As a result of this project, new technologies for DNA sequencing have improved in efficiency and cost by more than a millionfold over the past decade, and these technologies can now be routinely applied at a cost of less than $5,000 per genome. Although the application of these technologies in cancer genomics research has continued to contribute to basic discoveries, opportunities for translating them for individual patients have also emerged. This is especially important in clinical cancer research, where genetic alterations in a patient's tumor may be matched to molecularly targeted therapies. In this review, we discuss the integration of cancer genomics and clinical oncology and the opportunity to deliver precision cancer medicine.

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“…Despite the current emphasis on synergy, historically successful combinations were developed according to quite different hypotheses. For example, Law and Frei et al argued for combining drugs that are independently effective and have non-overlapping mechanisms of resistance (Frei et al, 1965;Law, 1956Law, , 1952. Such combinations are expected to overcome clonal heterogeneity present within each patient's cancer.…”

Section: Introductionmentioning

confidence: 99%

A curative combination therapy for lymphomas achieves high fractional cell killing through low cross-resistance and drug additivity but not synergy

Palmer

Chidley

Sorger

2018

Preprint

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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. Lymphoma (DLBCL). 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. The reasons for the clinical superiority of R-CHOP in DLBCL remain poorly understood. Pritchard et al. (2013) observed no synergy among pairs of drugs in CVAD (similar to CHOP) in a mouse cell line model of Non-Hodgkin lymphoma, and in profiling the effects of 93 gene knockdowns by RNA interference on drug sensitivity, the change in sensitivity to CVAD was equal (for almost every knockdown) to the average of its changes in single-drug sensitivity; this demonstrates that CVAD does not act as a more potent version of a single drug, nor does it exhibit a new signature of genetic dependencies.We tested for pharmacological interaction among all pairs of R-CHOP constituents across a full dose range in three DLBCL cell lines and assessed interaction using both the Bliss independence and Loewe additivity criteria. We observed little if any synergy: most drug pairs were additive and some were antagonistic. We also tested higher order combinations at fixed dose ratios with similar results. We then screened for cross resistant mutations using random mutagenesis with clone tracing as well as CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa) with genome-scale libraries. The rate of multi-drug resistance was near the theoretical minimum pr...

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The Effectiveness of Combinations of Antileukemic Agents in Inducing and Maintaining Remission in Children with Acute Leukemia

Cited by 279 publications

References 7 publications

Unexpectedly High Subclonal Mutational Diversity in Human Colorectal Cancer and Its Significance

Unexpectedly High Subclonal Mutational Diversity in Human Colorectal Cancer and Its Significance

Translating Genomics for Precision Cancer Medicine

A curative combination therapy for lymphomas achieves high fractional cell killing through low cross-resistance and drug additivity but not synergy

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