Enhancing the effect of Tumour necrosis factor - Related Apoptosis Inducing Ligand (TRAIL) in malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is a cancer which originates from the pleura, a layer lining the lungs. The prognosis is bleak as patients who receive standard of care chemotherapy have a median overall survival of approximately 12 months. Tumour necrosis factor - Related Apoptosis Inducing Ligand (TRAIL) is a protein involved in activating the extrinsic apoptosis pathway via engagement with death receptors located on the surface of cells. Following activation of this intracellular cascade, cells undergo apoptosis. We have previously shown that when MPM cells have loss of function mutations in BRCA-1 associated protein 1 (BAP1) they sensitise to TRAIL. BAP1 is involved in several other key cellular functions such as DNA damage response, cell cycle regulation, cell growth and differentiation. Moreover, TRAIL selectively seeks out transformed cells and activates apoptosis making this a therapy of great interest. Methods of utilising TRAIL include recombinant TRAIL (rTRAIL) or through lentiviral transduction of mesenchymal stromal cells expressing TRAIL on their surface (MSCTRAIL). The work I present in this thesis attempts to amplify the effect of TRAIL exploiting key areas that govern its function. I show in vitro that BAP1 plays a non-critical role in homologous recombination and by attempting to exploit this through synthetic lethality using PARP inhibition, a marginal differential response is seen between mutant and wild type cell lines. In addition, I explore the relationship between TRAIL and the immune system. I go on to show that a strong anti-tumour synergistic relationship exists between host immune cells and TRAIL, validated through the development of a syngeneic platform using pleural effusion derived cell lines and matched immune cells from the same patient. Finally, I present work evaluating the role of heat shock protein 90 (HSP90) inhibition and TRAIL confirming a synergistic relationship between the two

Perspectives on the Treatment of Malignant Pleural Mesothelioma

Malignant mesothelioma is an aggressive tumor arising from the serosal outer linings of the lungs (pleurae), heart, abdomen, and testes. Treatment trials have focused on malignant pleural mesothelioma, which accounts for 90% of cases, is often diagnosed at an advanced stage, and invariably leads to death. Malignant pleural mesothelioma has proved to be a formidable challenge for clinicians and scientists, with the 5-year survival rate continuing to languish at 5 to 10%.1 By far the most important risk factor for the development of malignant mesothelioma is asbestos exposure, although other risk factors, including related minerals, are beginning to emerge.2 The United States and other Western countries are seeing a gentle decline in cases of malignant mesothelioma as a result of transforming work practices. In the United States, age-adjusted mortality has been reduced from almost 14 deaths per 1 million persons in 2000 to 11 deaths per 1 million in 2015.3 Britain (England, Scotland, and Wales) has one of the highest death rates in the world at 77 deaths per 1 million (from 2017 to 2019), although this rate is also in decline.4 However, regional successes in prevention through eliminating clinically significant exposure to asbestos have not been matched by the development of new treatments.In this review, we reflect on the limited effect of the few positive phase 3 randomized, controlled studies, as well as recent trials examining the benefit of immunotherapy. We speculate about how rapid advances in our understanding of the genetics and biology of malignant pleural mesothelioma could translate into more effective therapies.</div

Ki-67 index and response to chemotherapy in patients with neuroendocrine tumours

Chemotherapy (CT) is widely used for neuroendocrine tumours (NETs), but there are no validated biomarkers to predict response. The Ki-67 proliferation index has been proposed as a means of selecting patients for CT, but robust data are lacking. The aim of this study was to investigate the relationship between response to chemotherapy and Ki-67 in NET. We reviewed data from 222 NET patients treated with CT. Tumours were graded according to Ki-67 index: G1 ≤2%, G2 3–20% and G3 >20%. Response was assessed according to RECIST and survival calculated from start of chemotherapy to death. To explore Ki-67 as a marker of response, we calculated the likelihood ratio and performed receiver operating characteristic analysis. Overall, 193 patients had a documented Ki-67 index, of which 173 were also evaluable for radiological response: 10% were G1, 46% G2 and 43% G3; 46% were pancreatic NET (PNET). Median overall survival was 22.1 months. Overall response rate was 30% (39% in PNET vs 22% in non-PNET) and 43% of patients had stable disease. Response rate increased with grade: 6% in G1 tumours, 24% in G2 and 43% in G3. However, maximum likelihood ratio was 2.3 at Ki-67=35%, and the area under the ROC curve was 0.60. As reported previously, a high Ki-67 was an adverse prognostic factor for overall survival. In conclusion, response to CT increases with Ki-67 index, but Ki-67 alone is an unreliable means to select patients for CT. Improved methods to stratify patients for systemic therapy are required

Acute immune signatures and their legacies in severe acute respiratory syndrome coronavirus-2 infected cancer patients

Given the immune system's importance for cancer surveillance and treatment, we have investigated how it may be affected by SARS-CoV-2 infection of cancer patients. Across some heterogeneity in tumor type, stage, and treatment, virus-exposed solid cancer patients display a dominant impact of SARS-CoV-2, apparent from the resemblance of their immune signatures to those for COVID-19+ non-cancer patients. This is not the case for hematological malignancies, with virus-exposed patients collectively displaying heterogeneous humoral responses, an exhausted T cell phenotype and a high prevalence of prolonged virus shedding. Furthermore, while recovered solid cancer patients' immunophenotypes resemble those of non-virus-exposed cancer patients, recovered hematological cancer patients display distinct, lingering immunological legacies. Thus, while solid cancer patients, including those with advanced disease, seem no more at risk of SARS-CoV-2-associated immune dysregulation than the general population, hematological cancer patients show complex immunological consequences of SARS-CoV-2 exposure that might usefully inform their care