establishing-physiologic-human-vascularized-micro-tumor-model-for

Establishing a Physiologic Human Vascularized Micro-Tumor Model for Cancer Research

A lack of validated cancer models that recapitulate the tumor microenvironment of solid cancers in vitro remains a significant bottleneck for preclinical ...

University of California, Irvine

Over the last decade, the treatment of metastatic melanoma has been revolutionized by the translation of molecular insights into therapeutic benefit for patients. These include advances in immunotherapeutic and small-molecule approaches aimed at destroying cells with immunogenic antigens or gene mutations. Despite these advances, the limited durability of clinical response and eventual disease progression underscores a need for better understanding of mechanisms underlying tumor development. Current targeted therapies are developed partly based on the rationale that tumors are primarily clonal with respect to mutant oncogene or cell surface antigen target. However, with the advancement of cell isolation and transplantation approaches coupled with deep sequencing and mutation detection techniques, it has become increasingly clear that tumors are polyclonal. As a result, sensitive malignant cells are eradicated by treatment while the remaining tumor cell populations are conferred varying degrees of resistance and survival advantages by harbouring or acquiring certain epigenetic and genetic abnormalities. Tumor heterogeneity thus represents a major obstacle to the successful application of current therapies. Gaining insights into the cellular and molecular aspects of tumor diversity will not only facilitate the development and selection of therapeutic targets but also promote the evolution of precision medicine. In this viewpoint, we will discuss the implications of tumor heterogeneity for the treatment of metastatic melanoma and propose approaches to accelerate the translation of scientific discovery into improved clinical outcomes.

Therapeutic implications of melanoma heterogeneity.

Over the past six decades the inflation-adjusted cost to bring a new drug to market has been increasing constantly and doubles every 9 years - now reaching in excess of $2.5 billion. Overall, the likelihood of FDA approval for a drug (any disease indication) that has entered phase I clinical trials is a mere 9.6%, with the approval rate for oncology far below average at only 5.1%. Lack of efficacy or toxicity is often not revealed until the later stages of clinical trials, despite promising preclinical data. This indicates that the current in vitro systems for drug screening need to be improved for better predictability of in vivo outcomes. Microphysiological systems (MPS), or bioengineered 3D microfluidic tissue and organ constructs that mimic physiological and pathological processes in vitro, can be leveraged across preclinical research and clinical trial stages to transform drug development and clinical management for a range of diseases. Here we review the current state-of-the-art in 3D tissue-engineering models developed for cancer research, with a focus on tumor-on-a-chip, or tumor chip, models. From our viewpoint, tumor chip systems can advance innovative medicine to ameliorate the high failure rates in anti-cancer drug development and clinical treatment.

Applications of tumor chip technology.

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the US. For the vast majority of patients with advanced CRC (ie, for those in whom metastatic tumors are unresectable), treatment is palliative and typically involves chemotherapy, biologic therapy, and/or immune checkpoint inhibition. In recent years, the use of adoptive T-cell therapy (ACT), leveraging the body's own immune system to recognize and target cancer, has become increasingly popular. Unfortunately, while ACT has been successful in the treatment of hematological malignancies, it is less efficacious in advanced CRC due in part to a lack of productive immune infiltrate. This systematic review was conducted to summarize the current data for the efficacy and safety of ACT in advanced CRC. We report that ACT is well tolerated in patients with advanced CRC. Favorable survival estimates among patients with advanced CRC receiving ACT demonstrate promise for this novel treatment paradigm. However, additional stage I/II clinical trials are needed to establish the efficacy and safety of ACT in patients with CRC.

Article	Year
Therapeutic implications of melanoma heterogeneity. Experimental dermatology\| PubMed ID: 27060971	2016
Applications of tumor chip technology. Lab on a chip\| PubMed ID: 30156248	2018
Adoptive T-Cell Therapy in Advanced Colorectal Cancer: A Systematic Review. The oncologist\| PubMed ID: 35274719	2022

Stephanie J. Hachey

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