Perspectives on the integration of Immuno-Oncology Biomarkers and drugs in a Health Care setting

Vermaelen, Karim; Waeytens, Anouk; Kholmanskikh, Olga; Bulcke, Marc Van den; Valckenborgh, Els Van

doi:10.1016/j.semcancer.2017.11.011

Cited by 11 publications

(12 citation statements)

References 79 publications

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“…This has had a tremendous impact on the therapy landscape in treating patients with advanced melanoma improving not only overall survival but leading to long-term survival in some patients. However, resistance to targeted therapies as well immunotherapy where bio-markers of response are not yet wellestablished [5,6], present challenges in the treatment of melanoma. Although combinatorial approaches of the various targeted therapies together with immunotherapies are underway [7], the high-costs [5] associated with immunotherapy highlights an urgent need for novel anti-melanoma therapeutic options.…”

Section: Introductionmentioning

confidence: 99%

“…However, resistance to targeted therapies as well immunotherapy where bio-markers of response are not yet wellestablished [5,6], present challenges in the treatment of melanoma. Although combinatorial approaches of the various targeted therapies together with immunotherapies are underway [7], the high-costs [5] associated with immunotherapy highlights an urgent need for novel anti-melanoma therapeutic options. The application of drugs used for alternate diseases as novel anti-cancer therapeutics, known as drug repositioning, has been successfully implemented in the clinical setting [8] and these compounds can be a rich potential source of novel, readily available anti-cancer therapeutics.…”

Section: Introductionmentioning

confidence: 99%

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Repurposing the serotonin agonist Tegaserod as an anticancer agent in melanoma: molecular mechanisms and clinical implications

Liu

Stachura

et al. 2020

J Exp Clin Cancer Res

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Background: New therapies are urgently needed in melanoma particularly in late-stage patients not responsive to immunotherapies and kinase inhibitors.Methods: Drug screening, IC50 determinations as well as synergy assays were detected by the MTT assay. Apoptosis using Annexin V and 7AAD staining was assessed using flow cytometry. TUNEL staining was performed using immunocytochemistry. Changes in phosphorylation of key molecules in PI3K/Akt/mTOR and other relevant pathways were detected by western blot as well as immunocytochemistry. To assess in vivo anti-tumor activity of Tegaserod, syngeneic intravenous and subcutaneous melanoma xenografts were used. Immunocytochemical staining was performed to detect expression of active Caspase-3, cleaved Caspase 8 and p-S6 in tumors. Evaluation of immune infiltrates was carried out by flow cytometry.Results: Using a screen of 770 pharmacologically active and/or FDA approved drugs, we identified Tegaserod (Zelnorm, Zelmac) as a compound with novel anti-cancer activity which induced apoptosis in murine and human malignant melanoma cell lines. Tegaserod (TM) is a serotonin receptor 4 agonist (HTR4) used in the treatment of irritable bowel syndrome (IBS). TM's anti-melanoma apoptosis-inducing effects were uncoupled from serotonin signaling and attributed to PI3K/Akt/mTOR signaling inhibition. Specifically, TM blunted S6 phosphorylation in both BRAF V600E and BRAF wildtype (WT) melanoma cell lines. TM decreased tumor growth and metastases as well as increased survival in an in vivo syngeneic immune-competent model. In vivo, TM also caused tumor cell apoptosis, blunted PI3K/Akt/mTOR signaling and decreased S6 phosphorylation. Furthermore TM decreased the infiltration of immune suppressive regulatory CD4 + CD25 + T cells and FOXP3 and ROR-γt positive CD4 + T cells. Importantly, TM synergized with Vemurafenib, the standard of care drug used in patients with late stage disease harboring the BRAF V600E mutation and could be additively or synergistically combined with Cobimetinib in both BRAF V600E and BRAF WT melanoma cell lines in inducing anti-cancer effects.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Repurposing the serotonin agonist Tegaserod as an anticancer agent in melanoma: molecular mechanisms and clinical implications

Liu

Stachura

et al. 2020

J Exp Clin Cancer Res

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“…There is now widespread recognition that immuno-oncological treatment strategies that target patient-specific tumor vulnerabilities and/or attempt to affect the complex interactions between tumor cells and the immune system will have an increasing impact on cancer care 1 - 4 . However, while subpopulations of patients are highly responsive, overall response rates are often low 5 , 6 , suggesting there is a substantial gap between laboratory understanding and the deployment of these treatment strategies in patients 7 . This is at least in part a consequence of an inability to both noninvasively assess the availability of drug targets and determine whether the administered drug engages the targets as expected 7 - 10 .…”

Section: Introductionmentioning

confidence: 99%

Noninvasive quantification of target availability during therapy using paired-agent fluorescence tomography

et al. 2020

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Immuno-oncological treatment strategies that target abnormal receptor profiles of tumors are an increasingly important feature of cancer therapy. Yet, assessing receptor availability (RA) and drug-target engagement, important determinants of therapeutic efficacy, is challenging with current imaging strategies, largely due to the complex nonspecific uptake behavior of imaging agents in tumors. Herein, we evaluate whether a quantitative noninvasive imaging approach designed to compensate for nonspecific uptake, MRI-coupled paired-agent fluorescence tomography (MRI-PAFT), is capable of rapidly assessing the availability of epidermal growth factor receptor (EGFR) in response to one dose of anti-EGFR antibody therapy in orthotopic brain tumor models. Methods: Mice bearing orthotopic brain tumor xenografts with relatively high EGFR expression (U251) (N=10) or undetectable human EGFR (9L) (N=9) were considered in this study. For each tumor type, mice were either treated with one dose of cetuximab, or remained untreated. All animals were scanned using MRI-PAFT, which commenced immediately after paired-agent administration, and values of RA were recovered using a model-based approach, which uses the entire dynamic sequence of agent uptake, as well as a simplified “snapshot” approach which requires uptake measurements at only two time points. Recovered values of RA were evaluated between groups and techniques. Hematoxylin & eosin (H&E) and immunohistochemical (IHC) staining was performed on tumor specimens from every animal to confirm tumor presence and EGFR status. Results: In animals bearing EGFR(+) tumors, a significant difference in RA values between treated and untreated animals was observed (RA = 0.24 ± 0.15 and 0.61 ± 0.18, respectively, p=0.027), with an area under the curve - receiver operating characteristic (AUC-ROC) value of 0.92. We did not observe a statistically significant difference in RA values between treated and untreated animals bearing EGFR(-) tumors (RA = 0.18 ± 0.19 and 0.27 ± 0.21, respectively; p = 0.89; AUC-ROC = 0.55), nor did we observe a difference between treated EGFR(+) tumors compared to treated and untreated EGFR(-) tumors. Notably, the snapshot paired-agent strategy quantified drug-receptor engagement within just 30 minutes of agent administration. Examination of the targeted agent alone showed no capacity to distinguish tumors either by treatment or receptor status, even 24h after agent administration. Conclusions: This study demonstrated that a noninvasive imaging strategy enables rapid quantification of receptor availability in response to therapy, a capability that could be leveraged in preclinical drug development, patient stratification, and treatment monitoring.

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“…Participation in external evaluation of the quality is a prerequisite before implementation by a laboratory of predictive biological tests for therapeutic response [ 9 , 10 , 11 ]. When considering the therapeutic issues, the benefit-risk balance for patients and the management of economic models related to public health, it is essential to use a reliable biomarker [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Any Place for Immunohistochemistry within the Predictive Biomarkers of Treatment in Lung Cancer Patients?

Hofman

Lassalle

Bence

et al. 2018

Cancers

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The identification of certain genomic alterations (EGFR, ALK, ROS1, BRAF) or immunological markers (PD-L1) in tissues or cells has led to targeted treatment for patients presenting with late stage or metastatic lung cancer. These biomarkers can be detected by immunohistochemistry (IHC) and/or by molecular biology (MB) techniques. These approaches are often complementary but depending on, the quantity and quality of the biological material, the urgency to get the results, the access to technological platforms, the financial resources and the expertise of the team, the choice of the approach can be questioned. The possibility of detecting simultaneously several molecular targets, and of analyzing the degree of tumor mutation burden and of the micro-satellite instability, as well as the recent requirement to quantify the expression of PD-L1 in tumor cells, has led to case by case development of algorithms and international recommendations, which depend on the quality and quantity of biological samples. This review will highlight the different predictive biomarkers detected by IHC for treatment of lung cancer as well as the present advantages and limitations of this approach. A number of perspectives will be considered.

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Perspectives on the integration of Immuno-Oncology Biomarkers and drugs in a Health Care setting

Cited by 11 publications

References 79 publications

Repurposing the serotonin agonist Tegaserod as an anticancer agent in melanoma: molecular mechanisms and clinical implications

Repurposing the serotonin agonist Tegaserod as an anticancer agent in melanoma: molecular mechanisms and clinical implications

Noninvasive quantification of target availability during therapy using paired-agent fluorescence tomography

Any Place for Immunohistochemistry within the Predictive Biomarkers of Treatment in Lung Cancer Patients?

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