Cell and gene therapy: a snapshot of investor perspectives

In a collaborative effort between the Commercialization Committee of the International Society for Cell & Gene Therapy (ISCT) and Bloomberg Intelligence, a broad survey of the investment community was executed in order to understand investor perceptions of companies that develop cell and gene therapies (CGTs) and gauge the trajectory of future investment. A broad spectrum of investors responded to the survey, including both health care specialists and generalist investors across a wide range of fund sizes and geographies. A majority of survey respondents have limited exposure to CGTs in their health care portfolios today, which highlights the opportunity to increase awareness of this burgeoning field in the investment community. The survey established that clinically significant data are the most important consideration when making an investment in this area, whereas safety concerns were highlighted as the most prominent barrier to making an investment. Challenges with manufacturing and scale-up were also ranked as a significant concern. The majority of investors hold the belief that both autologous and allogeneic cell therapies can co-exist. The detailed findings of this survey will help to provide a foundation for educational content that the ISCT Commercialization Committee can bring forth to further the investment in CGTs through the newly created Investigators to Investors program.     

In vivo chemoresistance of prostate cancer in metronomic cyclophosphamide therapy

A human prostate cancer (PC3) xenograft model was established which reflects acquired in vivo resistance towards metronomic cyclophosphamide (CPA) treatment. Cell cultures of two in vivo resistant PC3 tumors were established which maintain chemoresistant phenotypes upon xenografting into mice. A comparative proteome analysis of the two resistant cell lines PC3-D3 and -D4 versus the non-resistant parental PC3 cell line by 2D-DIGE approach followed by MALDI-TOF–TOF analysis revealed a total of 25 differently expressed proteins. Validation of protein candidates by Western blot analysis of the corresponding in vivo tumor xenografts identified three differentially expressed proteins (thioredoxin containing protein 5, cathepsin B, and annexin A3). Thioredoxin containing protein 5 was up-regulated in resistant xenografts only upon in vivo CPA therapy. A truncated version of cathepsin B translocated into mitochondria in the resistant clones whereas it stays cytoplasmic in corresponding parental PC3 cells. Annexin A3 (ANXA3) presents a very interesting candidate which was found to be up-regulated both in vitro and in xenografts, with protein levels further increased by metronomic CPA treatment in vivo. It is noteworthy that independent studies in other epithelial cancers recently identified ANXA3 as cancer progression and resistance marker.     

A snapshot of cancer in Chile: analytical frameworks for developing a cancer policy

Introduction

The South American country Chile now boasts a life expectancy of over 80 years. As a consequence, Chile now faces the increasing social and economic burden of cancer and must implement political policy to deliver equitable cancer care. Hindering the development of a national cancer policy is the lack of comprehensive analysis of cancer infrastructure and economic impact.

Objectives

Evaluate existing cancer policy, the extent of national investigation and the socio-economic impact of cancer to deliver guidelines for the framing of an equitable national cancer policy.

Methods

Burden, research and care-policy systems were assessed by triangulating objective system metrics – epidemiological, economic, etc. – with political and policy analysis. Analysis of the literature and governmental databases was performed. The oncology community was interviewed and surveyed.

Results

Chile utilizes 1% of its gross domestic product on cancer care and treatment. We estimate that the economic impact as measured in Disability Adjusted Life Years to be US$ 3.5 billion. Persistent inequalities still occur in cancer distribution and treatment. A high quality cancer research community is expanding, however, insufficient funding is directed towards disproportionally prevalent stomach, lung and gallbladder cancers.

Conclusions

Chile has a rapidly ageing population wherein 40% smoke, 67% are overweight and 18% abuse alcohol, and thus the corresponding burden of cancer will have a negative impact on an affordable health care system. We conclude that the Chilean government must develop a national cancer strategy, which the authors outline herein and believe is essential to permit equitable cancer care for the country.     

microRNA与肿瘤

microRNA（miRNA）是近年来发现的一类长度为19—25个核苷酸的非编码小分子RNA。它主要通过与靶标基因3’UTR的完全或不完全配对,降解靶标基因mRNA或抑制其翻译,从而参与调控个体发育、细胞凋亡、增殖及分化等生命活动。实验证据表明,miRNA可通过调控其靶标基因参与的信号通路,影响肿瘤的发生和发展,发挥着类似于癌基因或抑癌基因的功能。miRNA的发现为肿瘤发病机制的研究提供了新的思路,为肿瘤诊断和治疗提供了新的策略。本综述主要介绍近年来miRNA与肿瘤发生发展相关性研究领域的进展。     

Cell and gene therapy products in Malaysia: a snapshot of the industry's current regulation preparedness

Background aimsCell and gene therapy products (CGTPs) are anticipated to bring many benefits for the treatment of conditions with limited or no satisfactory treatment options. However, they are associated with concerns of potential safety risks because of their high complexity. The National Pharmaceutical Regulatory Agency (NPRA) of Malaysia took the first step toward the regulation of CGTPs by publishing the Malaysian Guidance Document and Guidelines for CGTPs in 2016. As mandatory registration and enforcement of CGTPs were scheduled to begin January 1, 2021, the aim of this study was to ascertain the industry's readiness for the regulation of CGTPs in terms of awareness of the guidelines, challenges and acceptance of the regulatory requirements.MethodsThe authors invited 48 CGTP companies to participate in the survey between October 2019 and June 2020, and 30 companies responded.ResultsThe majority of respondents were aware of the mandatory CGTP regulatory control and the availability of the guidelines. Many CGTPs were in the early development phase, and the most difficult registration barriers were dossier preparation and compliance with the pre-clinical and clinical requirements.ConclusionsThese findings represent the current CGTP landscape in Malaysia from the industry's viewpoint, enabling the NPRA to implement initiatives to facilitate registration and enforcement.     

Extracellular vesicles in ovarian cancer chemoresistance,metastasis, and immune evasion

Chemoresistance and metastasis are the major challenges for the current ovarian cancer treatment. Understanding the mechanisms of ovarian cancer progression and metastasis is critically important for developing novel therapies. The advances in extracellular vesicles (EVs) research in recent years have attracted extensive attention. EVs contain a variety of proteins, RNAs, DNAs, and metabolites. Accumulating evidence indicates that ovarian cancer cells secrete a large amount of EVs, playing an important role in tumor progression and recurrence. In the microenvironment of ovarian tumor, EVs participate in the information transmission between stromal cells and immune cells, promoting the immune escape of ovarian cancer cells and facilitating cancer metastasis. Here, we review the recent advances of EVs in chemoresistance, mechanisms of metastasis, and immune evasion of ovarian cancer. Furthermore, we also discuss the challenges of EV research and future application of EVs as promising biomarker sources in response to therapy and in therapy-delivery approaches for ovarian cancer patients.Subject terms: Cancer microenvironment, Translational research     

Apoptosis, chemoresistance, and breast cancer: insights from the MCF-7 cell model system

The MCF-7 cell line was derived from a patient with metastatic breast cancer in 1970. Since then it has become a prominent model system for the study of estrogen receptor-positive breast cancer. With this model as a focus, this review summarizes important studies addressing tumor necrosis factor-alpha as a prototypical apoptosis-inducing cytokine in MCF-7 cells. Both survival and death receptor signaling pathways are discussed in terms of their role in chemotherapy-induced apoptosis as well as in chemoresistance. Novel therapeutic approaches to the treatment of breast cancer are proposed utilizing knowledge of these signaling pathways as targets. Specifically, ceramide metabolism is proposed as a novel target for chemosensitivity, perhaps combined with selective inhibitors of Bcl-2 or PI3K/Akt/nuclear factor-kappaB. Suggested areas of future research include translational studies manipulating candidate survival and death signaling pathways.     

Interconnections between apoptotic,autophagic and necrotic pathways: implications for cancer therapy development

The rapid accumulation of knowledge on apoptosis regulation in the 1990s was followed by the development of several experimental anticancer‐ and anti‐ischaemia (stroke or myocardial infarction) drugs. Activation of apoptotic pathways or the removal of cellular apoptotic inhibitors has been suggested to aid cancer therapy and the inhibition of apoptosis was thought to limit ischaemia‐induced damage. However, initial clinical studies on apoptosis‐modulating drugs led to unexpected results in different clinical conditions and this may have been due to co‐effects on non‐apoptotic interconnected cell death mechanisms and the ‘yin‐yang’ role of autophagy in survival versus cell death. In this review, we extend the analysis of cell death beyond apoptosis. Upon introduction of molecular pathways governing autophagy and necrosis (also called necroptosis or programmed necrosis), we focus on the interconnected character of cell death signals and on the shared cell death processes involving mitochondria (e.g. mitophagy and mitoptosis) and molecular signals playing prominent roles in multiple pathways (e.g. Bcl2‐family members and p53). We also briefly highlight stress‐induced cell senescence that plays a role not only in organismal ageing but also offers the development of novel anticancer strategies. Finally, we briefly illustrate the interconnected character of cell death forms in clinical settings while discussing irradiation‐induced mitotic catastrophe. The signalling pathways are discussed in their relation to cancer biology and treatment approaches.     

DNA repair endonuclease ERCC1�CXPF as a novel therapeutic target to overcome chemoresistance in cancer therapy

The ERCC1–XPF complex is a structure-specific endonuclease essential for the repair of DNA damage by the nucleotide excision repair pathway. It is also involved in other key cellular processes, including DNA interstrand crosslink (ICL) repair and DNA double-strand break (DSB) repair. New evidence has recently emerged, increasing our understanding of its requirement in these additional roles. In this review, we focus on the protein–protein and protein–DNA interactions made by the ERCC1 and XPF proteins and discuss how these coordinate ERCC1–XPF in its various roles. In a number of different cancers, high expression of ERCC1 has been linked to a poor response to platinum-based chemotherapy. We discuss prospects for the development of DNA repair inhibitors that target the activity, stability or protein interactions of the ERCC1–XPF complex as a novel therapeutic strategy to overcome chemoresistance.