Opportunities and Challenges in the Development of Experimental Drug Combinations for Cancer

Humphrey, Rachel; Brockway-Lunardi, Laura; Bonk, David T.; Dohoney, Kathleen M.; Doroshow, James H.; Meech, Sandra J.; Ratain, Mark J.; Topalian, Suzanne L.; Pardoll, Drew M.

doi:10.1093/jnci/djr246

Cited by 106 publications

(77 citation statements)

References 20 publications

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“…There is currently sufficient evidence to conclude that KRAS mutant subpopulations are prevalent in advanced CRCs, and that such [5,19,[47][48][49]. As this investigation unfolds, it will be important to develop therapies that can specifically eliminate KRAS mutant cells, perhaps by direct killing based on synthetic lethality or by pharmaco logically driving oncogene-induced senescence.…”

Section: Resultsmentioning

confidence: 99%

KRAS Mutant Tumor Subpopulations can Subvert Durable Responses to Personalized Cancer Treatments

Parsons

Myers

2013

Personalized Medicine

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KRAS mutations in colorectal and lung cancers predict failure to respond to therapies that target the EGFR. Significant percentages of patients with KRAS wild-type tumors also fail to respond to these therapies. Relapse occurs in patients with KRAS wild-type and mutant tumors, with moderately longer progression-free survival in patients with KRAS wild-type tumors. Colon and lung tumors frequently carry KRAS mutant tumor subpopulations not detected by DNA sequencing. This suggests detected and undetected KRAS mutant subpopulations in colon and lung tumors are undermining the efficacy of anti-EGFR therapies. Therefore, consideration should be given to combining therapies that target KRAS mutant cells with those that downregulate EGFR signaling. As tumors are frequently polyclonal in origin and comprised of distinct clonal populations carrying complementing genetic and/or epigenetic lesions, preclinical models that assess the efficacy of combination therapies in the context of heterogeneous tumor cell populations will be essential for progress in this area.

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Section: Resultsmentioning

confidence: 99%

KRAS Mutant Tumor Subpopulations can Subvert Durable Responses to Personalized Cancer Treatments

Parsons

Myers

2013

Personalized Medicine

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“…Our increased understanding of the biology of cancer has allowed us to develop new approaches to treat this complex disease [9]. In chronic myeloid leukaemia (CML), the identification of a specific acquired genetic change involving a translocation between chromosome 9 and 22 that led to the production of a leukaemia-specific protein (BCR-ABL), fuelled the development of a targeted therapeutic strategic approach that delivered the tyrosine kinase inhibitor (TKI) imatinib mesylate; the Food and Drug Administration (FDA) and subsequent European Medicines Agency (EMA) approval of this TKI revolutionised the treatment of this disease [10].…”

Section: Cancer Clinical Trials: the Wheel Is Broken - So Let's Fix Itmentioning

confidence: 99%

“…While PPM has delivered significant advances as outlined above [9,10,11,12,13,14,15,16,35], a question that we must ask ourselves is - Can we afford it? A number of participants at the Institute of Medicine (IOM)-convened workshop ‘Affordable Cancer Care in the 21st Century' [36] highlighted their concerns on the financial sustainability of cancer care delivery.…”

Section: Converting Cost To Value: Charting a Pathway To Affordable Qmentioning

confidence: 99%

Personalised and Precision Medicine in Cancer Clinical Trials: Panacea for Progress or Pandora's Box?

Lawler¹,

Sullivan

2015

Public Health Genomics

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Cancer clinical trials have been one of the key foundations for significant advances in oncology. However, there is a clear recognition within the academic, care delivery and pharmaceutical/biotech communities that our current model of clinical trial discovery and development is no longer fit for purpose. Delivering transformative cancer care should increasingly be our mantra, rather than maintaining the status quo of, at best, the often miniscule incremental benefits that are observed with many current clinical trials. As we enter the era of precision medicine for personalised cancer care (precision and personalised medicine), it is important that we capture and utilise our greater understanding of the biology of disease to drive innovative approaches in clinical trial design and implementation that can lead to a step change in cancer care delivery. A number of advances have been practice changing (e.g. imatinib mesylate in chronic myeloid leukaemia, Herceptin in erb-B2-positive breast cancer), and increasingly we are seeing the promise of a number of newer approaches, particularly in diseases like lung cancer and melanoma. Targeting immune checkpoints has recently yielded some highly promising results. New algorithms that maximise the effectiveness of clinical trials, through for example a multi-stage, multi-arm type design are increasingly gaining traction. However, our enthusiasm for the undoubted advances that have been achieved are being tempered by a realisation that these new approaches may have significant cost implications. This article will address these competing issues, mainly from a European perspective, highlight the problems and challenges to healthcare systems and suggest potential solutions that will ensure that the cost/value rubicon is addressed in a way that allows stakeholders to work together to deliver optimal cost-effective cancer care, the benefits of which can be transferred directly to our patients.

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“…However, even if the right drug is identified, important issues still remain regarding its optimal dose. Despite the revolutionary changes in the various stages of drug development used for TKIs (Humphrey et al, 2011), the standard strategy still in use for dose selection is to establish a therapeutic dose in phase II trials and subsequently, at best, modify it for individual differences in body surface area in children. This is an unsustainable situation since failure to deliver the right dose in routine practice may have detrimental implications for both the efficacy and safety of TKIs Scheffler et al, 2011).…”

Section: Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

Uptake Carriers and Oncology Drug Safety

Sprowl

Sparreboom

2013

Drug Metab Dispos

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Members of the solute carrier (SLC) family of transporters are responsible for the cellular influx of a broad range of endogenous compounds and xenobiotics in multiple tissues. Many of these transporters are highly expressed in the gastrointestinal tract, liver, and kidney and are considered to be of particular importance in governing drug absorption, elimination, and cellular sensitivity of specific organs to a wide variety of oncology drugs. Although the majority of studies on the interaction of oncology drugs with SLC have been restricted to the use of exploratory in vitro model systems, emerging evidence suggests that several SLCs, including OCT2 and OATP1B1, contribute to clinically important phenotypes associated with those agents. Recent literature has indicated that modulation of SLC activity may result in drug-drug interactions, and genetic polymorphisms in SLC genes have been described that can affect the handling of substrates. Alteration of SLC function by either of these mechanisms has been demonstrated to contribute to interindividual variability in the pharmacokinetics and toxicity associated with several oncology drugs. In this report, we provide an update on this rapidly emerging field.

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Opportunities and Challenges in the Development of Experimental Drug Combinations for Cancer

Cited by 106 publications

References 20 publications

KRAS Mutant Tumor Subpopulations can Subvert Durable Responses to Personalized Cancer Treatments

KRAS Mutant Tumor Subpopulations can Subvert Durable Responses to Personalized Cancer Treatments

Personalised and Precision Medicine in Cancer Clinical Trials: Panacea for Progress or Pandora's Box?

Uptake Carriers and Oncology Drug Safety

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