Metronomic Chemotherapy Modulates Clonal Interactions to Prevent Drug Resistance in Non-Small Cell Lung Cancer

Bondarenko, Maryna; Grand, Marion Le; Shaked, Yuval; Raviv, Ziv; Chapuisat, Guillemette; Carrère, Cécile; Montero, Marie-Pierre; Rossi, Marie-Eva; Pasquier, Eddy; Carré, Manon; André, Nicolas

doi:10.3390/cancers13092239

Cited by 23 publications

(17 citation statements)

References 58 publications

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“…To comply with the 3-R rule, we used supernumerary mice (aged 12 weeks) that were destined to be sacrificed. A spheroid formed from DsRed-expressing MB cells [ 50 , 51 ] was then grafted onto each cerebellum slice. These organotypic co-culture models were placed on inserts and maintained as previously described [ 51 ].…”

Section: Methodsmentioning

confidence: 99%

Targeting of the ELR+CXCL/CXCR1/2 Pathway Is a Relevant Strategy for the Treatment of Paediatric Medulloblastomas

Penco-Campillo

Molina

Piris

et al. 2022

Cells

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Medulloblastoma (MB) is the most common and aggressive paediatric brain tumour. Although the cure rate can be as high as 70%, current treatments (surgery, radio- and chemotherapy) excessively affect the patients’ quality of life. Relapses cannot be controlled by conventional or targeted treatments and are usually fatal. The strong heterogeneity of the disease (four subgroups and several subtypes) is related to innate or acquired resistance to reference treatments. Therefore, more efficient and less-toxic therapies are needed. Here, we demonstrated the efficacy of a novel inhibitor (C29) of CXCR1/2 receptors for ELR+CXCL cytokines for the treatment of childhood MB. The correlation between ELR+CXCL/CXCR1/2 expression and patient survival was determined using the R2: Genomics Analysis and Visualization platform. In vitro efficacy of C29 was evaluated by its ability to inhibit proliferation, migration, invasion, and pseudo-vessel formation of MB cell lines sensitive or resistant to radiotherapy. The growth of experimental MB obtained by MB spheroids on organotypic mouse cerebellar slices was also assayed. ELR+CXCL/CXCR1/2 levels correlated with shorter survival. C29 inhibited proliferation, clone formation, CXCL8/CXCR1/2-dependent migration, invasion, and pseudo-vessel formation by sensitive and radioresistant MB cells. C29 reduced experimental growth of MB in the ex vivo organotypic mouse model and crossed the blood–brain barrier. Targeting CXCR1/2 represents a promising therapeutic strategy for the treatment of paediatric MB in first-line treatment or after relapse following conventional therapy.

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Section: Methodsmentioning

confidence: 99%

Targeting of the ELR+CXCL/CXCR1/2 Pathway Is a Relevant Strategy for the Treatment of Paediatric Medulloblastomas

Penco-Campillo

Molina

Piris

et al. 2022

Cells

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“…However, they develop more slowly compared to the MTD regimen, which could be due to the multimodal character of the former [20,48]. In this regard, it has been demonstrated that MC modulates the balance of drug-resistant and drug-sensitive clones co-existing within a tumor better than an MTD regimen [49]. Cancer cells and host cells develop tumor support mechanisms to escape therapy.…”

Section: Metronomic Chemotherapy: a Multimodal Therapymentioning

confidence: 99%

Metronomic Anti-Cancer Therapy: A Multimodal Therapy Governed by the Tumor Microenvironment

Muñoz

Girotti

Hileeto

et al. 2021

Cancers

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The concept of cancer as a systemic disease, and the therapeutic implications of this, has gained special relevance. This concept encompasses the interactions between tumor and stromal cells and their microenvironment in the complex setting of primary tumors and metastases. These factors determine cellular co-evolution in time and space, contribute to tumor progression, and could counteract therapeutic effects. Additionally, cancer therapies can induce cellular and molecular responses in the tumor and host that allow them to escape therapy and promote tumor progression. In this study, we describe the vascular network, tumor-infiltrated immune cells, and cancer-associated fibroblasts as sources of heterogeneity and plasticity in the tumor microenvironment, and their influence on cancer progression. We also discuss tumor and host responses to the chemotherapy regimen, at the maximum tolerated dose, mainly targeting cancer cells, and a multimodal metronomic chemotherapy approach targeting both cancer cells and their microenvironment. In a combination therapy context, metronomic chemotherapy exhibits antimetastatic efficacy with low toxicity but is not exempt from resistance mechanisms. As such, a better understanding of the interactions between the components of the tumor microenvironment could improve the selection of drug combinations and schedules, as well as the use of nano-therapeutic agents against certain malignancies.

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“…They reported the biologically optimal dose as a periodically increasing dose titration. Recently, a theoretical study by Ledzewicz 28 and another in vitro study by Bondarenko et al 29 also reported a biologically optimal dose 5 to reduce resistance. However, all existing literature addresses the issue of the optimal dose in theoretical or experimental settings.…”

Section: Introductionmentioning

confidence: 98%

Containing Cancer with Personalized Minimum Effective Dose

Masud

Kim

2022

Preprint

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Resistance to treatment is a challenge in many cancer therapies. This is partly due to the heterogeneous nature of tumors, where drug-sensitive and drug-resistant cells compete for the same resources. This competition is largely shaped by cancer treatment. The rapid reduction of drug-sensitive cell population during therapy with a maximum-tolerated dose relaxes competitive stress on the drug-resistant cell population, promoting relapse. Therefore, maintaining a high level of drug-sensitive cell population with a treatment break or lower dose can impose effective competitive stress on drug-resistant cell populations. Adaptive therapy (AT) exploits the competition between cancer cells. However, given the heterogeneous treatment response of individual patients, determining a personalized optimal treatment that can fine-tune competitive stress remains challenging. Using a deterministic model of cancer cell population competition, this study defines an effective dose window (EDW) as a range of doses that conserve sufficient sensitive cells, while maintaining the tumor volume below a threshold (e.g., initial tumor volume), to maintain a sustained competition against resistant cells. As a proof of concept, we sought to determine the EDW for a small cohort of patients with melanoma (n=8). We first fitted the model to longitudinal tumor response data from each patient. We performed structural and practical identifiability analyses to confirm the reproducibility and uniqueness of the estimated parameters. Then, we considered a subset of the cohort with uniquely identifiable parameters and estimated patient-specific EDW. We demonstrated that if the dose belongs to the EDW, the tumor volume for each patient could be indefinitely contained either using continuous or AT strategy. Using the optimal control theory, we concluded that the lower bound of the EDW approximates the minimum effective dose (MED) for containing cancer. Taken together, using tumor biomarker data, this study provides a proof of concept that there may exist a patient-specific EDW that keeps the tumor below a threshold (e.g., initial volume) by maintaining sustained competition on resistant cells.

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Metronomic Chemotherapy Modulates Clonal Interactions to Prevent Drug Resistance in Non-Small Cell Lung Cancer

Cited by 23 publications

References 58 publications

Targeting of the ELR+CXCL/CXCR1/2 Pathway Is a Relevant Strategy for the Treatment of Paediatric Medulloblastomas

Targeting of the ELR+CXCL/CXCR1/2 Pathway Is a Relevant Strategy for the Treatment of Paediatric Medulloblastomas

Metronomic Anti-Cancer Therapy: A Multimodal Therapy Governed by the Tumor Microenvironment

Containing Cancer with Personalized Minimum Effective Dose

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