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Dual Epidermal Growth Factor Inhibition and Multi Targeted Epigenetic Therapy (MTET)

Journal of Cancer Therapy 2018年第11期9卷 872-882页

作者： Mohammad Nezami steve hager Pacific Medical Center of Hope and Research Cancer Institute of America Fresno CA USA

Since the discovery of tyrosine kinase inhibitors in treatment of lung cancer harboring such actionable targets, many lives have been prolonged. To the same extent, same group of patients have failed to benefit from this category of drugs, in long run, either initially or during the course of treatments, simply due to either known or unknown mechanism of resistance which occurs very often in the first few months after initiation of therapy. The resistance is 100 percent expected, and no patient is reported to be a waiver of such pattern. With best practices of oncology, the average duration of response is expected to be below 12 months [1]. About half of the resistance is caused by mutation at T790M in EGFR target, which can be revealed by liquid biopsy [1] [2]. The most recent studies have revealed the significant role of epigenome in controlling this complicated resistance pattern. We have learned that Histone deacetylation, as opposed to promoter methylation, may contribute to the epigenetic silencing and to EGFR TKI resistance in NSCLC [3] [4]. Here we present a case study with a model of combinational therapy that targets the EGFR molecule, (by small molecule inhibitor, Afatanib) with simultaneous epigenetic modification of the target, (by application of multitargeted epigenetic therapy (MTET) with significantly improved clinical results. We propose further trials are needed to support such hypothesis, which if proved, could significantly shift the current practices in management of this set of cases in lung adenocarcinomas.

关键词： Epidermal Growth Factor Lung Cancer Epigenetic Therapies Targeted Therapies Afatinib

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Evidence Based Medicine, in Precision Oncology

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Journal of Cancer Therapy 2018年第9期9卷 689-705页

作者： M. Nezami steve hager Pacific Medical Center of Hope Fresno USA

The disagreements in clinical data and therapy recommendations extracted from different sources/studies are a common finding in oncology research. Knowingly “biology is less reproducible than physics and mechanic engineering”, in order to overcome the disagreements and to find common grounds, we still rely on meta-analysis and systemic reviews for the highest level of evidence. To gather systemic review data base, a bibliographic search usually is conducted in the PubMed and in Cochrane Central Register of Controlled Trials databases to address a common clinical challenge. That said, frequently due to common conflicts between articles outcomes, an opinion of a third investigator is sought. Here in this article, we propose a rationale that could explain the differences in outcomes as a result of imperfect understanding of the current research database secondary to the unique biology of the tumor, rather than statistical interpretation on findings. We believe that the differences in findings merely are based on blinded inclusion criteria, and lack of accurate companion diagnostics to correlate the magnitude of response to each therapy. The objective of this article is to discuss a strategy to overcome such discordance by providing quantitative biological measures for genomic classification and correlation of tumor response to the selected targeted therapy. We further review such analysis in a case series of Her 2 positive breast cancer and conclude that translational research would be clinically relevant when customized to the biological findings.

关键词： Breast Cancer Her/Neu 2 Cancer Targeted Therapies Precision Oncology Epigenetic Therapies

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Biological Modulation of Parp Inhibition in Triple Negative Breast Cancer, a Combinational Approach Implementing Multitargeted Epigenetic Therapy (Mtet) with Parp Inhibition, in Advanced Breast Cancer: A Case Study

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Journal of Cancer Therapy 2018年第9期9卷 729-739页

作者： M.Nezami steve hager Julie Taguchi Pacific Medical Center of Hope FresnoUSA

The introduction of PARP inhibitors as active agents to inhibit the DNA repair was a revolution in the cancer therapeutics, however, such approach only has shown promising results for a short time in majority of cases due to secondary mutations and promoter gene methylation, and most of patients with triple negative breast cancer when treated with such agents only benefit for a short time, until the tumor shows resistance and further the therapy fails [1]. Considering this category of drugs and their mechanism of action in DNA repair [2] [3], several recent studies have focused on combination of PARP inhibitors with chemotherapy, immune therapy and interestingly relevant to this article, epigenetic therapies [4]. That said, to our knowledge the human data in this regard is missing. Here we discuss a case report of a patient with stage four refractory and resistant BRCA1 mutated triple negative breast cancer who responded in matter of two weeks to a combinational therapy, consisting of PARP inhibitor and epigenetic therapies. As the patient already had exhausted the PARP inhibitor by excessive presence of BRCA positive altered circulatory DNA, the response merely reflects the epigenetic therapy as back bone of treatment. The liquid biopsy repeated after two weeks of combination therapy showed complete disappearance (resolution of positive BRCA gene/c DNA), reflecting a synergism by proposed modulation of resistance as mechanism of action. (The initial c DNA showed 93 percent mutation allele fraction of BRCA gene.) To our knowledge, this is the first study on combinational therapy in human. The finding in this case could potentially change the standard of care in treating BRCA positive tumors, by providing a superior treatment to current standards.

关键词： Triple Negative Breast Cancer PARP Inhibition Epigenetic Therapies

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