Mutations in the TP53 tumour suppressor gene are very frequent in cancer, and attempts to restore the functionality of p53 in tumours as a therapeutic strategy began decades ago. However, very few of these drug development programmes have reached late-stage clinical trials, and no p53-based therapeutics have been approved in the USA or Europe so far. This is probably because, as a nuclear transcription factor, p53 does not possess typical drug target features and has therefore long been considered undruggable. Nevertheless, several promising approaches towards p53-based therapy have emerged in recent years, including improved versions of earlier strategies and novel approaches to make undruggable targets druggable. Small molecules that can either protect p53 from its negative regulators or restore the functionality of mutant p53 proteins are gaining interest, and drugs tailored to specific types of p53 mutants are emerging. In parallel, there is renewed interest in gene therapy strategies and p53-based immunotherapy approaches. However, major concerns still remain to be addressed. This Review re-evaluates the efforts made towards targeting p53-dysfunctional cancers, and discusses the challenges encountered during clinical development. 

https://www.nature.com/articles/s41573-022-00571-8.pdf

Drugging p53 in cancer: one protein, many targets

Ovarian cancer is a malignant tumor of the female reproductive system, with a very poor prognosis and high mortality rates. Chemotherapy and radiotherapy are the most common treatments for ovarian cancer, with unsatisfactory results. Exosomes are a subpopulation of extracellular vesicles, which have a diameter of approximately 30–100 nm and are secreted by many different types of cells in various body fluids. Exosomes are highly stable and are effective carriers of immunotherapeutic drugs. Recent studies have shown that exosomes are involved in various cellular responses in the tumor microenvironment, influencing the development and therapeutic efficacy of ovarian cancer, and exhibiting dual roles in inhibiting and promoting tumor development. Exosomes also contain a variety of genes related to ovarian cancer immunotherapy that could be potential biomarkers for ovarian cancer diagnosis and prognosis. Undoubtedly, exosomes have great therapeutic potential in the field of ovarian cancer immunotherapy. However, translation of this idea to the clinic has not occurred. Therefore, it is important to understand how exosomes could be used in ovarian cancer immunotherapy to regulate tumor progression. In this review, we summarize the biomarkers of exosomes in different body fluids related to immunotherapy in ovarian cancer and the potential mechanisms by which exosomes influence immunotherapeutic response. We also discuss the prospects for clinical application of exosome-based immunotherapy in ovarian cancer.

/pdf/exosomes-a-potential-tool-for-immunotherapy-of-ovarian-2lc228pm.pdf

Exosomes: A potential tool for immunotherapy of ovarian cancer

TP53 is a tumor suppressor gene that encodes a sequence-specific DNA-binding transcription factor activated by stressful stimuli; it upregulates target genes involved in growth suppression, cell death, DNA repair, metabolism, among others. TP53 is the most frequently mutated gene in tumors, with mutations not only leading to loss-of-function (LOF), but also gain-of-function (GOF) that promotes tumor progression, and metastasis. The tumor-specific status of mutant p53 protein has suggested it is a promising target for cancer therapy. We summarize the current progress of targeting wild-type and mutant p53 for cancer therapy through biotherapeutic and biopharmaceutical methods for (1) boosting p53 activity in cancer, (2) p53-dependent and p53-independent strategies for targeting p53 pathway functional restoration in p53-mutated cancer, (3) targeting p53 in immunotherapy, and (4) combination therapies targeting p53, p53 checkpoints, or mutant p53 for cancer therapy.

/pdf/advanced-strategies-for-therapeutic-targeting-of-wild-type-1s27wpcm.pdf

Advanced Strategies for Therapeutic Targeting of Wild-Type and Mutant p53 in Cancer

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that selectively induces apoptosis in tumor cells without harming normal cells, making it an attractive agent for cancer therapy. TRAIL induces apoptosis by binding to and activating its death receptors DR4 and DR5. Several TRAIL-based treatments have been developed, including recombinant forms of TRAIL and its death receptor agonist antibodies, but the efficacy of TRAIL-based therapies in clinical trials is modest. In addition to inducing cancer cell apoptosis, TRAIL is expressed in immune cells and plays a critical role in tumor surveillance. Emerging evidence indicates that the TRAIL pathway may interact with immune checkpoint proteins, including programmed death-ligand 1 (PD-L1), to modulate PD-L1-based tumor immunotherapies. Therefore, understanding the interaction between TRAIL and the immune checkpoint PD-L1 will lead to the development of new strategies to improve TRAIL- and PD-L1-based therapies. This review discusses recent findings on TRAIL-based therapy, resistance, and its involvement in tumor immunosurveillance. 

/pdf/the-role-of-trail-in-apoptosis-and-immunosurveillance-in-37v9pb69.pdf

The Role of TRAIL in Apoptosis and Immunosurveillance in Cancer

Colorectal cancer (CRC) is one of the most common cancers worldwide. Current therapies such as surgery, chemotherapy, and radiotherapy encounter obstacles in preventing metastasis of CRC even when applied in combination. Immune checkpoint inhibitors depict limited effects due to the limited cases of CRC patients with high microsatellite instability (MSI-H). Cancer vaccines are designed to trigger the elevation of tumor-infiltrated lymphocytes, resulting in the intense response of the immune system to tumor antigens. This review briefly summarizes different categories of CRC vaccines, demonstrates the current outcomes of relevant clinical trials, and provides particular focus on recent advances on nanovaccines and neoantigen vaccines, representing the trend and emphasis of CRC vaccine development.

/pdf/colorectal-cancer-vaccines-the-current-scenario-and-future-36uo6vz7.pdf

Colorectal cancer vaccines: The current scenario and future prospects

Though early-stage colorectal cancer has a high 5 year survival rate of 65-92% depending on the specific stage, this probability drops to 13% after the cancer metastasizes. Frontline treatments for colorectal cancer such as chemotherapy and radiation often produce dose-limiting toxicities in patients and acquired resistance in cancer cells. Additional targeted treatments are needed to improve patient outcomes and quality of life. Immunotherapy involves treatment with peptides, cells, antibodies, viruses, or small molecules to engage or train the immune system to kill cancer cells. Preclinical and clinical investigations of immunotherapy for treatment of colorectal cancer including immune checkpoint blockade, adoptive cell therapy, monoclonal antibodies, oncolytic viruses, anti-cancer vaccines, and immune system modulators have been promising, but demonstrate limitations for patients with proficient mismatch repair enzymes. In this review, we discuss preclinical and clinical studies investigating immunotherapy for treatment of colorectal cancer and predictive biomarkers for response to these treatments. We also consider open questions including optimal combination treatments to maximize efficacy, minimize toxicity, and prevent acquired resistance and approaches to sensitize mismatch repair-proficient patients to immunotherapy. 

/pdf/immunotherapy-for-colorectal-cancer-mechanisms-and-2jnp4gzp.pdf

Immunotherapy for Colorectal Cancer: Mechanisms and Predictive Biomarkers

The discovery of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) along with its potent and selective antitumor effects initiated a decades-long search for therapeutic strategies to target the TRAIL pathway. First-generation approaches were focused on the development of TRAIL receptor agonists (TRAs), including recombinant human TRAIL (rhTRAIL) and TRAIL receptor-targeted agonistic antibodies. While such TRAIL pathway-targeted therapies showed promise in preclinical data and clinical trials have been conducted, none have advanced to FDA approval. Subsequent second-generation approaches focused on improving upon the specific limitations of first-generation approaches by ameliorating the pharmacokinetic profiles and agonistic abilities of TRAs as well as through combinatorial approaches to circumvent resistance. In this review, we summarize the successes and shortcomings of first- and second-generation TRAIL pathway-based therapies, concluding with an overview of the discovery and clinical introduction of ONC201, a compound with a unique mechanism of action that represents a new generation of TRAIL pathway-based approaches. We discuss preclinical and clinical findings in different tumor types and provide a unique perspective on translational directions of the field. 

Therapeutic targeting of TRAIL death receptors

Editor's evaluation: Arbidol inhibits human esophageal squamous cell carcinoma growth in vitro and in vivo through suppressing ataxia telangiectasia and Rad3-related protein kinase

Editor's evaluation: Detection of malignant peripheral nerve sheath tumors in patients with neurofibromatosis using aneuploidy and mutation identification in plasma

Editor's evaluation: Paracrine signalling between intestinal epithelial and tumour cells induces a regenerative programme

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