Is combination therapy the next step to overcome resistance and reduce toxicities in melanoma?

Nijenhuis, Cynthia M.; Haanen, John B.A.G.; Schellens, Jan H.M.; Beijnen, Jos H.

doi:10.1016/j.ctrv.2012.10.006

Cited by 14 publications

(7 citation statements)

References 77 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One important aspect of combination therapy is the potential for synergistic effects. Other benefits compared to single-agent treatment include higher overall efficacy, lower exposure to the drugs and thereby improved safety, reduced toxicity, and lower risk of developing drug resistances (2)(3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

Tumor Static Concentration Curves in Combination Therapy

Cardilin

Almquist

Jirstrand

et al. 2016

AAPS J

View full text Add to dashboard Cite

Abstract.Combination therapies are widely accepted as a cornerstone for treatment of different cancer types. A tumor growth inhibition (TGI) model is developed for combinations of cetuximab and cisplatin obtained from xenograft mice. Unlike traditional TGI models, both natural cell growth and cell death are considered explicitly. The growth rate was estimated to 0.006 h −1 and the natural cell death to 0.0039 h −1 resulting in a tumor doubling time of 14 days. The tumor static concentrations (TSC) are predicted for each individual compound. When the compounds are given as single-agents, the required concentrations were computed to be 506 μg · mL −1 and 56 ng · mL −1 for cetuximab and cisplatin, respectively. A TSC curve is constructed for different combinations of the two drugs, which separates concentration combinations into regions of tumor shrinkage and tumor growth. The more concave the TSC curve is, the lower is the total exposure to test compounds necessary to achieve tumor regression. The TSC curve for cetuximab and cisplatin showed weak concavity. TSC values and TSC curves were estimated that predict tumor regression for 95% of the population by taking between-subject variability into account. The TSC concept is further discussed for different concentration-effect relationships and for combinations of three or more compounds.

show abstract

Section: Introductionmentioning

confidence: 99%

Tumor Static Concentration Curves in Combination Therapy

Cardilin

Almquist

Jirstrand

et al. 2016

AAPS J

View full text Add to dashboard Cite

show abstract

“…Although phase II clinical trials of the BRAF/MEK inhibitor combination have shown increased PFS compared to BRAF inhibitor alone, resistance is still widespread (12;18-20). There is already good evidence of cross-resistance between BRAF and MEK inhibitors, suggesting similar mechanisms of resistance (13-17).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of HSP90 by AT13387 Delays the Emergence of Resistance to BRAF Inhibitors and Overcomes Resistance to Dual BRAF and MEK Inhibition in Melanoma Models

Smyth¹,

Paraiso

Hearn³

et al. 2014

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Emergence of clinical resistance to BRAF inhibitors, alone or in combination with MEK inhibitors, limits clinical responses in melanoma. Inhibiting HSP90 offers an approach to simultaneously interfere with multiple resistance mechanisms. Using the HSP90 inhibitor, AT13387, which is currently in clinical trials, we investigated the potential of HSP90 inhibition to overcome or delay the emergence of resistance to these kinase inhibitors in melanoma models. In vitro, treating vemurafenib-sensitive cells (A375 or SK-MEL-28) with a combination of AT13387 and vemurafenib prevented colony growth under conditions where vemurafenib treatment alone generated resistant colonies. In vivo, when AT13387 was combined with vemurafenib in a SK-MEL-28, vemurafenib-sensitive model, no regrowth of tumors was observed over 5 months, although 2 out of 7 tumors in the vemurafenib monotherapy group relapsed in this time. Together these data suggest that the combination of these agents can delay the emergence of resistance. Cell lines with acquired vemurafenib resistance, derived from these models (A375R, SK-MEL-28R) were also sensitive to HSP90 inhibitor treatment; key clients were depleted, apoptosis was induced and growth in 3D-culture was inhibited. Similar effects were observed in cell lines with acquired resistance to both BRAF and MEK inhibitors (SK-MEL-28RR, WM164RR, 1205LuRR). These data suggest that treatment with an HSP90 inhibitor, such as AT13387, is a potential approach for combatting resistance to BRAF and MEK inhibition in melanoma. Moreover, frontline combination of these agents with an HSP90 inhibitor could delay the emergence of resistance, providing a strong rationale for clinical investigation of such combinations in BRAF-mutated melanoma.

show abstract

“…By targeting the disease along multiple pathways, the increasing problem of drug resistance can be reduced . There is also a potential for drug synergies . Synergistic interactions can take many forms.…”

mentioning

confidence: 99%

Model‐Based Evaluation of Radiation and Radiosensitizing Agents in Oncology

Cardilin

Almquist

Jirstrand

et al. 2017

CPT Pharmacom & Syst Pharma

View full text Add to dashboard Cite

Radiotherapy is one of the major therapy forms in oncology, and combination therapies involving radiation and chemical compounds can yield highly effective tumor eradication. In this paper, we develop a tumor growth inhibition model for combination therapy with radiation and radiosensitizing agents. Moreover, we extend previous analyses of drug combinations by introducing the tumor static exposure (TSE) curve. The TSE curve for radiation and radiosensitizer visualizes exposure combinations sufficient for tumor regression. The model and TSE analysis are then tested on xenograft data. The calibrated model indicates that the highest dose of combination therapy increases the time until tumor regrowth 10‐fold. The TSE curve shows that with an average radiosensitizer concentration of 1.0 normalμboldg/boldmboldL the radiation dose can be decreased from 2.2 boldGboldy to 0.7 boldGboldy. Finally, we successfully predict the effect of a clinically relevant treatment schedule, which contributes to validating both the model and the TSE concept.

show abstract

Is combination therapy the next step to overcome resistance and reduce toxicities in melanoma?

Cited by 14 publications

References 77 publications

Tumor Static Concentration Curves in Combination Therapy

Tumor Static Concentration Curves in Combination Therapy

Inhibition of HSP90 by AT13387 Delays the Emergence of Resistance to BRAF Inhibitors and Overcomes Resistance to Dual BRAF and MEK Inhibition in Melanoma Models

Model‐Based Evaluation of Radiation and Radiosensitizing Agents in Oncology

Contact Info

Product

Resources

About