Programmed cell death (PCD) or apoptosis is a mechanism which is crucial for all multicellular organisms to control cell proliferation and maintain tissue homeostasis as well as eliminate harmful or unnecessary cells from an organism. Defects in the physiological mechanisms of apoptosis may contribute to different human diseases like cancer. Identification of the mechanisms of apoptosis and its effector proteins as well as the genes responsible for apoptosis has provided a new opportunity to discover and develop novel agents that can increase the sensitivity of cancer cells to undergo apoptosis or reset their apoptotic threshold. These novel targeted therapies include those targeting anti-apoptotic Bcl-2 family members, p53, the extrinsic pathway, FLICE-inhibitory protein (c-FLIP), inhibitor of apoptosis (IAP) proteins, and the caspases. In recent years a number of these novel agents have been assessed in preclinical and clinical trials. In this review, we introduce some of the key regulatory molecules that control the apoptotic pathways, extrinsic and intrinsic death receptors, discuss how defects in apoptotic pathways contribute to cancer, and list several agents being developed to target apoptosis.

https://www.koreascience.or.kr:443/article/JAKO201528551641815.pdf

Molecular Mechanisms of Apoptosis and Roles in Cancer Development and Treatment

Survivin (also known as BIRC5) is an evolutionarily conserved eukaryotic protein that is essential for cell division and can inhibit cell death. Normally it is only expressed in actively proliferating cells, but is upregulated in most, if not all cancers; consequently, it has received significant attention as a potential oncotherapeutic target. In this Cell Science at a Glance article and accompanying poster, we summarise our knowledge of survivin 21 years on from its initial discovery. We describe the structure, expression and function of survivin, highlight its interactome and conclude by describing anti-survivin strategies being trialled.

Survivin at a glance

The importance of personalized medicine has been growing, mainly due to a more urgent need to avoid unnecessary and expensive treatments. In nuclear medicine, the theranostic approach is an established tool for specific molecular targeting, both for diagnostics and therapy. The visualization of potential targets can help predict if a patient will benefit from a particular treatment. Thanks to the quick development of radiopharmaceuticals and diagnostic techniques, the use of theranostic agents has been continually increasing. In this article, important milestones of nuclear therapies and diagnostics in the context of theranostics are highlighted. It begins with a well-known radioiodine therapy in patients with thyroid cancer and then progresses through various approaches for the treatment of advanced cancer with targeted therapies. The aim of this review was to provide a summary of background knowledge and current applications, and to identify the advantages of targeted therapies and imaging in nuclear medicine practices.

/pdf/theranostics-in-nuclear-medicine-practice-4r1f8eajj8.pdf

Theranostics in nuclear medicine practice.

Apoptosis, a physiological process of programmed cell death, is disrupted in various malignancies. It has been exploited as an anti-cancer strategy traditionally by inducing DNA damage with chemotherapy and radiotherapy. With an increased understanding of the intrinsic and extrinsic pathways of apoptosis in recent years, novel approaches of targeting the apoptotic pathways have been tested in pre-clinical and clinical models. There are several early phase clinical trials investigating the therapeutic role of pro-apoptotic agents, both as single agents and in combination. In this review, we examine such treatment strategies, detailing the various compounds currently under clinical investigation, their potential roles in cancer therapeutics, and discussing approaches to their optimal use in the clinic.

Cancer therapeutics: Targeting the apoptotic pathway

Survivin (also named BIRC5) is a well-known cancer therapeutic target. Since its discovery more than two decades ago, the use of survivin as a target for cancer therapeutics has remained a central goal of survivin studies in the cancer field. Many studies have provided intriguing insight into survivin’s functional role in cancers, thus providing promise for survivin as a cancer therapeutic target. Despite this, moving survivin-targeting agents into and through the clinic remains a challenge. In order to address this challenge, we may need to rethink current strategies in order to develop a new mindset for targeting survivin. In this Review, we will first summarize the current survivin mechanistic studies, and then review the status of survivin cancer therapeutics, which is classified into five categories: (i) survivin-partner protein interaction inhibitors, (ii) survivin homodimerization inhibitors, (iii) survivin gene transcription inhibitors, (iv) survivin mRNA inhibitors and (v) survivin immunotherapy. We will then provide our opinions on cancer therapeutics using survivin as a target, with the goal of stimulating discussion that might facilitate translational research for discovering improved strategies and/or more effective anticancer agents that target survivin for cancer therapy.

/pdf/cancer-therapeutics-using-survivin-birc5-as-a-target-what-2obf17skn6.pdf

Cancer therapeutics using survivin BIRC5 as a target: what can we do after over two decades of study?

A phase II study of YM155, a novel small-molecule suppressor of survivin, in castration-resistant taxane-pretreated prostate cancer

Background: Up to 40% of hepatocellular carcinoma (HCC) patients have tumours driven by activating β-Catenin and canonical Wnt pathway mutations. Activated β-Catenin/canonical Wnt signalling is associated with primary resistance to standard of care immune checkpoint blockade mediated through immune cell excluded ‘cold’ tumour microenvironment. Recruitment of β-Catenin to canonical-Wnt target genes requires transducin beta-like protein 1 (TBL1) to activate transcription. The aim of this study was to test if small molecule inhibition of the TBL1:β-Catenin interaction is a tractable therapy in activated β-Catenin/canonical Wnt HCC and characterise its immunomodulatory effects upon the ‘cold’ immune microenvironment. Materials and methods: Using a genetically engineered C57BL/6J mouse model (GEMM) of β-Cateninexon3 mutant HCC, we tested the effects of TBL1 inhibition with the small molecule inhibitor, Tegavivint in either early or late stage disease. Littermates were randomised to receive either Tegavivint or vehicle control. We measured tumour number, volume and used immunohistochemistry to characterise the immune microenvironment and the expression of TBL1 and canonical Wnt target genes. Results: In untreated, β-Cateninexon3 mutant HCC GEMMs, TBL1 expression was identified specifically in tumour epithelium at early and late stages of tumour development. Inhibition of TBL1 in early-stage disease significantly reduced the number of tumour initiating clones identified by markers of canonical Wnt activation (Glutamine Synthetase, GS) compared with vehicle controls. Treatment of established β-Cateninexon3 activated tumours with Tegavivint inhibited tumour growth and resulted in a reduced tumour burden compared with vehicle controls. Furthermore, in mice with established tumours, Tegavivint treatment increased CD3+ T-lymphocyte tumour infiltration, with prominent increases in intratumoural CD8+ T-cells. Tegavivint treatment of mice with activated β-Cateninexon3 signalling throughout the entire liver significantly inhibited upregulation of canonical Wnt target genes (Glul, Axin2, Notum). In intestinal tissue, which depends on canonical Wnt signalling to maintain tissue homeostasis, we did not observe off target effects. Conclusions: Overall, this study suggests the TBL1:β-Catenin interaction is critical in the initiation of and maintaining growth of β-Cateninexon3 mutant HCC. Tegavivint therapy reduced tumour growth and lead to increased T-lymphocyte infiltration into the previously ‘immune-cold’ tumour microenvironment. Taken together, disruption of TBL1 and β-Catenin may provide a new precision therapy for β-Catenin mutant HCC. Further studies are underway to identify whether Tegavivint may be a useful therapy for immune checkpoint inhibitor refractory HCC. Conflict of interest: Corporate-sponsored Research: Iterion therapeutics supplied the compound for this study. Other Substantive Relationships: Kimberly Holloway, Stephen Horrigan, Jean Chang and Rahul Aras are employees of Iterion Therapeutics. 

The TBL1 inhibitor, Tegavivint, suppresses tumour growth and enhances T-cell infiltration in preclinical murine β-Catenin mutant hepatocellular carcinoma

T. Drake

Papers

A phase II study of YM155, a novel small-molecule suppressor of survivin, in castration-resistant taxane-pretreated prostate cancer

The TBL1 inhibitor, Tegavivint, suppresses tumour growth and enhances T-cell infiltration in preclinical murine β-Catenin mutant hepatocellular carcinoma