Sir Peter MacCallum Department of Oncology - Theses
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ItemThe evolutionary history of genes and transcriptional networks reveals fundamental properties of cancer associated with the breakdown of multicellularity( 2018)All biological systems follow the rules and constraints imposed during their evolution. Current-day gene phenotypes such as gene expression, gene essentiality, gene function and protein localization are linked with the time of evolutionary emergence of genes. In cancer, tumours rely on cellular processes that date back to unicellular ancestors (e.g., cell replication, glycolysis), while dysregulating key pathways linked to the emergence of multicellularity, suggesting that the transition from unicellularity to multicellularity left vulnerabilities in cells that act as guiding principles during cancer development. Therefore, in this thesis I integrate genomics, systems biology and evolutionary biology to investigate fundamental principles of tumourigenesis related to the evolutionary history of genes using gene expression and somatic mutation information across multiple tumour types. First, I coupled the evolutionary age of genes and cellular processes with their expression levels in tumour and normal samples, and found that tumours consistently activate genes from unicellular ancestors while switching off genes related to multicellularity. These consistent patterns were supported by a mutual exclusivity between the activity of genes and transcriptional networks of unicellular and multicellular ancestors, which promoted convergent evolution towards a state of loss of multicellularity. Second, I investigated how somatic mutations disrupted gene regulatory networks. Genes that emerged together with early metazoans were enriched in point mutations and copy- number alterations, indicating that gene innovations that took place at the onset of multicellularity play a fundamental role in cancer development. Importantly, the uncoupling of regulatory networks of unicellular and multicellular ancestors was mostly due to point mutations in gene regulators linking these networks. On the other hand, copy-number aberrations were directly involved in the activation and inactivation of unicellular and multicellular genes, suggesting point mutations and copy-number aberrations play complementary roles in the loss of regulation between unicellular and multicellular transcriptional networks in cancer. Third, I focused on novel transcriptional associations formed during tumourigenesis using gene co-expression module analysis. Significant levels of rewiring between unicellular and multicellular genes were found across tumours. This rewiring was mostly driven by gene amplifications, which promoted the formation of tumour-specific modules composed of novel transcriptional associations between unicellular and multicellular genes, once more linking the genes and regulatory associations evolved at the onset of multicellularity to cancer development. The findings of this work reveal fundamental principles driving cancer development associated with genes and transcriptional networks evolved during the transition from unicellularity to multicellularity. I propose a model whereby activation of programs that date back to unicellular ancestors and the deactivation of multicellular programs is driven by an inherent mutual exclusivity of these genes together with the breakage of regulation between unicellular and multicellular genes by point mutations, whereas the formation of novel transcriptional associations between these genes in tumours is driven by copy-number changes. Finally, I identify potential novel drivers based on their key role in uncoupling unicellular and multicellular transcriptional networks across tumours and suggest novel treatment strategies derived from this evolutionary approach. The results presented in this thesis contribute to our understanding of how past evolutionary events led to vulnerabilities in transcriptional networks that influence cancer development, and highlight the benefits of the integration of evolutionary concepts with genomics and network biology to identify fundamental principles of cancer.
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ItemHow information technology improves the quality and efficiency of medical care and research( 2018)In 2007, the concept of rapid learning healthcare was proposed in the United States of America health system in a response to increasing healthcare costs. Its aim was to accelerate knowledge discovery through a systematic approach to integrating electronic medical records design with analysis infrastructure to rapidly and continuously assess health system performance. The delivery of healthcare is becoming increasingly performed and documented within the electronic domain, and large databases of healthcare-related information being created as a by-product. This has led to an unprecedented level of access to detailed and structured clinical data that could be used to accelerate research. In a rapid learning healthcare system, the high level of integration from electronic record to policy would ensure that each patient and each click of the mouse would drive innovation. The attraction of rapid learning was not to supplant the traditional clinical trial paradigm, but to augment its effectiveness with accelerated analysis of real-world outcomes. The rapid learning concept relied heavily on electronic medical records, administrative systems and disease registries as data sources to power analyses. Electronic health record penetrance in Australia has lagged that achieved in the USA, primarily because of financial assistance provided as part of the HITECH act in the USA. However, one exception is seen in oncology, where radiotherapy is exclusively prescribed electronically. Additionally, there has been a significant shift toward electronic chemotherapy prescribing due to the clinical risk associated with manual systems. Perhaps in oncology there is an opportunity to replicate the successes of data-driven health research achieved elsewhere. The objective of the work contained in this thesis is to develop practical methods to expand and discover the infrastructure required to implement rapid learning health care in the Australian oncology context. Ultimately, the aim is to increase the quality and efficiency of medical care and research by harnessing novel information technology (IT) methods. In addition to leveraging existing secondary databases for health services research and creating high impact linkages with state-level cancer registries, advanced IT methods could also be used to automate manual data extraction tasks in a timely and cost-effective fashion. The integration of these methods into routine clinical practice has enormous implications for tracking patient care quality, and accelerating research by utilising all data by-products of health care.
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ItemInvestigating acquired resistance to Pol I transcription inhibitors for the treatment of haematologic malignancies( 2018)Previous work from our group and others has demonstrated that CX-5461 (Senhwa Biosciences), a first-in-class small molecule inhibitor of RNA Polymerase I transcription of the ribosomal RNA genes, is effective at treating a range of different cancers both in vitro and in vivo, and is currently in clinical trials for haematologic and solid tumours. However, despite initial tumour clearance in response to CX-5461 treatment in preclinical murine models of cancer, mice eventually relapse with tumours that are resistant to further CX-5461 treatment. This thesis investigates the mechanisms via which the tumours can develop resistance to CX-5461 treatment and extrapolates this research to better understand: 1) how CX-5461 functions as an anti-tumour agent; 2) which pathways are required to mediate resistance to CX-5461; and 3) how resistance can be overcome with combination therapy. Using DNA exome sequencing, we found that Top2α is frequently mutated in tumours that have acquired resistance to CX-5461 treatment in vivo. Functional characterization of a Top2α mutant cell line demonstrated that Top2α expression and activity were reduced in these cells. Indeed, we found that knockdown of Top2α was sufficient to cause resistance to CX-5461. This implies that Top2α could provide a novel biomarker for CX-5461 response in clinical trials. Further investigation of the CX-5461 resistance mechanism uncovered that CX-5461 also acts as a Top2 inhibitor in addition to its ability to inhibit rDNA transcription. However, unlike common chemotherapeutic Top2 inhibitors which kill cells by causing genome-wide DNA damage thereby initiating a DNA damage response, CX-5461 treatment causes comparatively fewer DNA breaks enriched at the ribosomal DNA promoter loci. Thus, CX-5461 is able to kill tumour cells via the DNA damage response in the absence of extensive DNA damage thereby potentially limiting the cytotoxicity of drug treatment. Together, the work presented in this thesis identifies novel mechanisms of action and resistance to CX-5461. We propose that CX-5461 and other second-generation inhibitors of RNA Polymerase I and Top2α may provide a viable, less genotoxic alternative to classic Top2 inhibitors.
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ItemPragmatic, consensus-based minimum standards and structured interview to guide the selection and development of cancer support group leaders( 2018)Across the globe, peer support groups have emerged as a community-led approach to connecting people with cancer experiences and accessing support. Members of cancer support groups seek to help themselves and each other to reduce the negative or disabling effect that cancer may have on general health, relationships, coping, and daily functioning. With no centralised registry, the number of cancer support groups is unknown but thought to be considerable. Peak cancer agencies have established relationships with support groups, in an effort to strengthen and sustain delivery of peer support. Agency funding, training, resources, and support staff are extended to groups, with the group leader being the primary recipient and point of contact. Group leadership is usually provided voluntarily by people with a personal experience of cancer. Challenges have been reported in maintaining group leaders’ quality of life and preventing burn-out. The ability of an individual to function in the role and maintain this role over a period of time is important for group sustainability. However, little is known about the essential qualities required to lead a cancer support group, or how to determine a person’s suitability for the role. Initial scoping of the literature revealed the lack of a relevant role analysis and no accurate synopsis of the basic knowledge, skills, and attributes required for the group leader role. There are no published guidelines, standards, or tools to guide selection and development of peer support group leaders. This project aimed to generate pragmatic, consensus-based minimum standards for the cancer support peer group leader role, and to develop a structured interview and user manual to guide the selection and development of cancer support group leaders. The interview was anchored in a comprehensive role analysis and validities were maximised by increasing structure in process and use of the interview data. Following a systematic review of research relevant to the desirable qualities for support group leaders, an online Delphi study was used to reach expert-consensus on the 52 knowledge, skills, and attributes considered essential for cancer support group leaders. These 52 requisite knowledge, skills, and attributes describe the minimum standards for the role, and were used to develop the structured interview. The structured interview and accompanying user manual were piloted for aspects of clinical utility and determined to be appropriate, accessible, practical, and acceptable for use by cancer agency workers. The structured interview was field tested with 63 current support group leaders to determine a potential cut-off score for selection of group leader’s suitability. However, a more comprehensive pool of participants and scores are required to determine reasonable cut-off scores. This PhD project used pragmatic, novel, and robust methods to respond to a real-world problem. Our study outputs are a first in the field, with scope for future research and development to apply the structured interview more broadly.