DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP)

DSI/NRF (Department of Science and Innovation/National Research Foundation) SARChI Chair in Precision Oncology and Cancer Prevention (POCP)

(Directed Area: Prevention and Precision Oncology to Universally Improve Cancer Outcomes)

HOST: Pan African Cancer Research Institute (PACRI), University of Pretoria

Co-Host: Center for Cancer Sciences, University of Nottingham, United Kingdom

SARChI Chair: Professor Zodwa Dlamini

Pan African Cancer Research Institute (PACRI), University of Pretoria, 0028

Email: [email protected]

RATIONALE OF THE CHAIR

Cancer rates continue to increase world-wide and it is the second leading cause of death globally with approximately 70% of cancer deaths occurring in low middle income countries (LMICs) [1,2]. Cancer is also emerging as a major public health problem in sub-Saharan Africa (SSA) and a high residual burden of HIV/AIDS, HPV, HBV in certain SSA countries being key drivers for about one-third of all cancers in the region [3]. Persistent infection with cancer risk-related viruses leads to changes in molecular, cellular and host immune response resulting in malignant transformation [4].

The four key risk factors for these cancers are tobacco use, alcohol excess, unhealthy diet and physical inactivity. The most common risk factor for liver cancer is chronic hepatitis B and C [4]. These infections lead to liver cirrhosis, the commonest pre- cancerous condition with regards to hepatocellular carcinoma (HCC). Alcohol excess, smoking, obesity, type 2 diabetes with fatty liver are also linked to HCC [5]. Exposure to aflatoxins is an additional risk factor for HCC in Africa. The Chair will focus on early detection and precision medicine in cancers linked to their risk factors, including lung (linked with smoking and COPD), liver (cirrhosis, viral hepatitis), cervical (HPV infection), colorectal, and breast cancer (linked with obesity, HIV, HPV, alcohol, and genetic predisposition), prostate cancer (pre-cancerous lesions).

We will evaluate community based screening programs including improved versions of existing systems such as mammography and HPV detection, as well as implementation of newer biomarker algorithms (using Gender, Age and 3 serologic biomarkers of AFP, AFP- L3, and Des-g- carboxyprothrombin; GALAD) [6-8], faecal immunochemistry test (FIT), molecular technologies of liquid biopsy (Paralogue ratio test (PRT) tailored for the detection of specific hotspot somatic copy number alterations; SCNAs) [9-10] and EarlyCDT (Lung) for community based risk stratification[11]. We will make use of the drastic reduction in cost and increased accessibility of sequencing technologies in South Africa (SA) (as demonstrated during the COVID pandemic) to implement precision medicine technologies that are applicable to SA to improve early therapeutic approaches for cancer treatment.

The long-term impact of this Chair is to improve health outcomes and reduce health inequalities, capacity building for early detection and precision oncology, strengthened health systems and the long-term sustainable growth of the Africa research ecosystem and strengthening economic development meeting the UN Sustainable Development Goals. The Chair will provide a platform for sustainable growth of the African research ecosystem by engaging in research capacity strengthening objectives as well as clinical, community and policy needs in key priority areas.

The Chair will invest in the development of critical mass of sustainable applied health research capacity at local level as well as to increase the number of internationally competitive African researchers and research institutions in Africa. In parallel, the Chair aims to drive African region-appropriate health improvements and promote socioeconomic development and will focus upon African-led research which responds to African population needs, will develop effective solutions, engage with African communities and policymakers to inform policy and practice. This will enable historically disadvantaged, less-research intensive institutions to expand their research capability and to move into new areas of research in support of South Africa and the African region health and research strategies.

OBJECTIVES

Objective 1. Determine, trial and test early detection mechanisms for cancer in at risk patients in South Africa using novel liquid biopsy, digital pathology, and Artificial Intelligence (AI) informed screening. This will span from molecular and radiological testing to community-based projects and public health and policy initiatives. Objective 1 will consist of seven arms:

Early detection of lung cancer using autoantibody screening, AI and remote assessment of CT scanning in patients with symptomatic lung disease (long term smokers, chronic cough, long-Covid, COPD).
Early detection of liver cancer in high-risk patients (viral hepatitis B and cirrhosis) through innovative surveillance technologies, GALAD algorithm and PRT tailored to detect SCNA
Enhanced breast screening programs though enhanced tele-mammography and AI informed scanning, and combined ctDNA liquid biopsy in HIV positive subjects.
Implementation of home testing kits for vaginal HPV to enhance screening uptake, aligned with AI mediated digital pathology screening to enhance early detection of cervical cancers.
Pilot evaluation of FIT in a South African setting in vulnerable populations followed by flexible sigmoidoscopy in community settings.
Enhancing prostate cancer screening through AI-aided combinatorial prostate sonography and serological (PSA coupled to kallikrein marker) testing.
Provide public health awareness, prevention and public education on cancer research.

Objective 2. Identify genome and transcriptome therapeutic vulnerabilities in South African patients to enhance precision medicine approaches in an African setting. Objective 2 will implement a precision medicine pipeline for cancer therapy at the University of Pretoria, to determine whether this can be rolled out in a LMIC setting.

Develop a pipeline for genomic and transcriptomic sequencing of major cancer types as they are diagnosed, and alignment with targeted therapies.
Implement this pipeline to develop basket trials of novel mutations in the South African population of repurposed drugs.
Build an in vitro cell culture facility that enables ex vivo real time testing of cancers against known targeted therapeutics to inform clinical practice.
Combining early community-based detection, stratification (PRT for SCNAs) and intervention (flexible sigmoidoscopy) in the community.

Short Term Specific Objectives (within 2 years)

Develop at risk registers through local health clinics in Gauteng province for patients at risk of lung and liver cancers (LTS, COPD, long-COVID, Viral hepatitis B & C and cirrhosis).
Build public awareness programs for screening research for breast, cervical, prostate and colorectal cancers.
Working with local health clinics, obtain ethics approval for, and initiate pilot clinical trials for lung cancer screening in at risk populations using EarlyCDT blood tests followed by CT screening for positive patients.
Initiate digital AI training program for mammography tele-screening and build capacity for widespread screening throughout Gauteng province. Obtain ethics approval for trial in section B.
Obtain ethics approval, plan and implement pilot trial of home testing for HPV from self- administered vaginal swabs. Build capacity for cervical screening by pathologists through tele-digital pathology.
Initiate a pilot trial of FIT screening in a disadvantaged population group in Gauteng province. 6.Initiate an AI-aided pilot screening for prostate cancer combining ultrasound and serological evaluation.
Develop the expertise and capacity to screen ex vivo cancer cells genetically and pharmacologically.
Enroll trainees in clinical trial, genomic, cell biology, public health, AI and digital pathology programs.
Provide public health awareness and prevention by offering educational programs on cancer research

Medium Term Specific Objectives: 2-3 years

Implementation of lessons learned from AI to areas in other parts of South Africa.
Initiate a large-scale trial of lung cancer screening comparing CT screening on symptoms with blood tests aligned to the ECLS study in Scotland.
Undertake a trial of tele screening versus standard mammography screening with and without AI training.
Run large scale trial of home HPV testing followed by tele-digital pathology compared with standard smear tests.
Expand FIT test to rural areas by expanding to Limpopo (LP), KwaZulu-Natal (KZN) and Eastern Cape (EC) Provinces using local University laboratories in Polokwane/Mankweng Hospital (Limpopo), Inkosi Albert Luthuli Hospital (KZN) and Dorah Nginza Hospital (EC) followed by community based flexible sigmoidoscopy.
Plan, obtain ethics, and apply for funding of a trial of molecularly targeted therapies in patients identified from susceptibility in vitro versus standard therapy.
Trial community-based surveillance and stratification of HCC using GALAD and PRT for SCNAs in the Gauteng Province (GP).
Run a large-scale trial of implementation of a digital pathology pipeline for prostate cancer integrating ultrasound and serological with clinical and molecular/omics evaluation for the patients, monitor benign hyperplasia at the same time, to corroborate changes in the genetic architectural differences and how these echoes in morphological parameters in Gauteng Province (GP).
Identify specific differences in South African cancer genome and transcriptome compared with publicly available databases from the US/UK.
Work with South African government to create clinical leads for these programs at the end of the program.

Long Term Specific Objectives (4-5 years)

Graduation of initial cohorts of trainees. Appointment into centrally funded posts to oversee trial outcomes and implementation.
Complete enrolments on lung, breast, colorectal, prostate and cervical cancer trials.
Initiate and enroll to basket treatment trial.
Complete the build of the African Cancer Genome Atlas (ACGA) and plan studies to investigate risk and susceptibility databases for African cancers.

EXPECTED OUTCOMES

Cancers in South Africa, and particularly in the disadvantaged communities, have different drivers from those in high income countries. Infections such as hepatitis B & C, HPV, HIV and Epstein Barr Virus drive cancers with different aetiologies from those in high income countries, resulting in different molecular and cellular sensitivities, age profiles at diagnosis, and aggressiveness. Moreover, screening technologies in high income countries are often not applicable in low-income environments and screening is often not undertaken in disadvantaged areas, despite a real need for screening in younger patients (e.g., age of onset of colorectal cancer and breast cancer is lower in black South Africans than

white South Africans, an indication of socioeconomic status, not race). This research is aimed specifically at piloting/evaluating screening, early diagnosis and treatments for areas of South Africa where economic development is lower with a view to be able to roll this out across other areas of South Africa and the African region, once successful. Program therefore squarely meets to sustainable development goals compliance.

Many cancers are preventable and curable if diagnosed early but locally over a third of our patients present at an advanced stage and die from the disease. Also, most of these patients presenting with early onset cancer, the aetiology is unknown. Neither a familial nor a hereditary syndrome can be identified as the cause thus highlighting a major gap in cancer research in South Africa and the region. There is paucity of local literature on the molecular profiling of many cancers not only in relation to their clinico-pathological features, but also whether there is a correlation with HIV, which is highly prevalent in South Africa. We aim to identify molecular targets and new clinically actionable cancer biomarkers and molecular targets. These would in future inform the development of high sensitivity and specificity tests for local cancer screening programs, early detection, prevention and the development of novel therapeutic agents.

The long-term impact of this Chair is to contribute to improved health outcomes, capacity building for early detection and precision oncology and strengthened health systems in South Africa and ultimately the African region.

REFERENCES

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World Health Organization. The top 10 causes of death. Geneva, WHO, 2018.
Parkin MD, Bray F, Ferlay J, Pisani P (2002), Global Cancer Statistics, 2002.
American Cancer Society, Liver Cancer Causes, Risk Factors, and Prevention, 2019.
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