The BTRI is a new initiative of the Department of Science and Technology initiated by the CSIR and the University of Cape Town (UCT) in the translation of biomedical research. The initiative aims to bring scientists from a number of institutions to work in close proximity with each other in a biomedical research environment, with access to an academic hospital and medical school to support translational research. The flagship project of the BTRI is a Precision Medicine project supported by the Medical Research Council of South Africa. It makes use of several advanced cutting edge molecular diagnostic, imaging tools, systems & synthetic biology tools to permit highly precise cancer diagnostics, matching tumor to appropriate drug regimens. In the future this will lead to gene-based therapies, treatments, diagnostics, training, education, and lead to job creation for scientists in South Africa.

Key Facts On Cancer Worldwide

Cancers figure among the leading causes of morbidity and mortality worldwide, with approx. 14 million new cases and 8.2 million cancer related deaths in 2012

The number of new cases is expected to rise by about 70% over the next two decades (to about 22 million)

Among men, the 5 most common sites of cancer diagnosed in 2012 were lung, prostate, colorectal, stomach, and liver cancer deaths in 2012

Among women, the 5 most common sites diagnosed were breast, colorectal, lung, cervix, and stomach cancer

Around one third of cancer deaths are due to the 5 leading behavioral and dietary risks: high body mass index, low fruit and vegetable intake, lack of physical activity, tobacco and alcohol use

Cancer causing viral infections such as HBV/HCV and HPV are responsible for up to 20% of deaths in low- and middle-income countries

More than 60% of world’s total new cases occur in Africa, Asia and Central and South America. These regions account for 70% of the world’s cancer deaths

Key Facts On Cancer in South Africa

Cancers figure among the leading causes of morbidity and mortality worldwide, with approx. 14 million new cases and 8.2 million cancer related deaths in 2012

The number of new cases is expected to rise by about 70% over the next two decades (to about 22 million)

Among men, the 5 most common sites of cancer diagnosed in 2012 were lung, prostate, colorectal, stomach, and liver cancer deaths in 2012

Among women, the 5 most common sites diagnosed were breast, colorectal, lung, cervix, and stomach cancer

Around one third of cancer deaths are due to the 5 leading behavioral and dietary risks: high body mass index, low fruit and vegetable intake, lack of physical activity, tobacco and alcohol use

Cancer causing viral infections such as HBV/HCV and HPV are responsible for up to 20% of deaths in low- and middle-income countries

More than 60% of world’s total new cases occur in Africa, Asia and Central and South America. These regions account for 70% of the world’s cancer deaths

Geographic Distribution of Noncommunicable Disease Burden

Geographic Distribution of Cancer Disease Burden

Geographic Distribution of Breast Cancer

Cancer prevalence in Africa

Estimated Cases (Male)

Prostate 39,500
Liver 34,600
Kaposi Sarcoma 22,400
Non-Hodgkin Lymphoma 21,900
Lung & Bronchus 20,800
Colon & Rectum 19,000
Esophagus 17,500
Urinary Bladder 16,900
Stomach 12,600
Leukemia 11,200
All sites but skin 324,700

Estimated Deaths (Male)

Liver 33,800
Prostate 28,000
Lung & Bronchus 19,400
Kaposi Sarcoma 19,100
Non-Hodgkin Lymphoma 18,100
Esophagus 16,700
Colon & Rectum 14,700
Stomach 11,900
Urinary Bladder 11,400
Leukemia 10,600
All sites but skin 267,200

Estimated Cases (Females)

Female Breast 92,600
Cervix Uteri 80,400
Liver 16,900
Colon & Rectum 15,800
Non-Hodgkin Lymphoma 15,300
Ovary 14,000
Kaposi Sarcoma 12,400
Esophagus 10,400
Stomach 10,100
Leukemia 8,300
All sites but skin 390,700

Estimated Deaths (Females)

Cervix Uteri 53,300
Female Breast 50,000
Liver 16,600
Non-Hodgkin Lymphoma 12,700
Colon & Rectum 12,300
Kaposi Sarcoma 10,500
Ovary 10,400
Esophagus 9,900
Stomach 9,500
Leukemia 7,800
All sites but skin 274,800

Breast Cancer Mortality Rates

What is Precision Medicine in Oncology?

Precision medicine aims to identify genomic & epigenetic changes and patterns in individual cancers that may influence therapy outcomes.

This form of research can yield treatment options for those patients whose cancer is not responding favourably to standard therapy.

Genomic information has shaped the development and use of some of the newest cancer treatments. Some examples are:

  1. imatinib (Gleevec) was designed to inhibit an alteredenzymeproduced by a fused version of twogenesfound inchronic myelogenous leukemia
  2. trastuzumab (Herceptin), which works only for women whose breast tumors have a particular genetic profile called HER-2 positive
  3. lung cancer patients whose tumors are positive forEGFRmutations respond to the drugs gefitinib (Iressa) and erlotinib (Tarceva) which target this mutation
  4. colon cancer patients whose tumors have a mutation in a gene called KRAS derive little benefit from the drugs cetuximab (Erbitux) and panitumumab
    (Vectibix).

The latest precision therapies coax the immune system to respond to cancer. These are so called checkpoint therapies. Currently only one is approved:

  1. PD-1/PD-1L (Keytruda and Opdiva) are humanized antibodies used in cancer immunotherapy. They target the programmed cell death 1 receptor or ligand. The drugs were initially used in treating metastatic melanoma

They work best when a companion diagnostic determines enriched PD-1R on tumor cells.

The type of genomic information generated by precision medicine will drive research to develop similar treatment strategies that will be most effective for a given set of genomic changes. By thus identifying potent markers of disease, immunotherapy selectively targeting these markers is becoming an integral part of precision medicine.

Since genetic variants are important in determination of therapeutic variants, the population in which oncology drugs are developed plays a critical role in determining gene-drug associations.

Sub-saharan Africa has populations with the highest genetic variation in the world and yet form the smallest cohort of individuals used in oncology therapeutic studies

Genome-wide SNP data from more than 100 populations worldwide comparing genes and geography finds significant similarity between genes and geography exists. A Quantitative Comparison of the Similarity between Genes and Geography in Worldwide Human Populations. August 23, 2012DOI: 10.1371/ journal.pgen.1002886

This means gene-drug association studies, the key to precision medicine, will need to be conducted in local geographies taking into account local genetic variation.

Key Facts on Breast Cancer in South Africa

Most frequent cancer among women: age-standardized incidence rate 27 per 100.000

Mortality: 3100 deaths in 2013, 16% of all cancer deaths in women

Majority of women present with late stage disease

Low levels of breast cancer knowledge and awareness

Molecular disease with genetic etiology significantly differing from individual to individual with genetic variants different from those in Europe & N. America

African population with world wide greatest degree of genetic diversity

Precision Medicine For Oncology in SA

Major aims: stage 1

To link African genomic diversity provided by analysis of primary probes of patients via genomic and epigenetic approaches with approved targeted therapeutic regimens.

Create a “living biobank” of South African tumors with variants unique to this geography. This will be made available to scientists, oncologists and pharma/biotech companies.

To use the data generated to introduce precision medicine based solutions for cancer-specific treatments flanked by appropriately adjusted companion diagnostics to provide treatment with highest probability of success for each and every patient.

Populate and curate a database where information on South African cancer genomics and therapeutic outcomes is widely accessible.

Proposed workflow for “living biobanks” in SA

Currently in pilot phase where we use colon and breast cancer to establish essential basic technologies including:

Routine ex vivo cultivation of tumor organoids, and long-term tumor banking

Establishment of genomic and epigenetic analyses

Stratification by immunological phenotyping

Identification of genetic variants of tumors linked to clinical outcome

Expanded Workflow For “Living Biobanks” in SA

Breast Cancer is Common and Fatal Cancer in Women

The Effect of Anti-Cancer Treatment is Not Uniform

Organoids Maintain Cancer Heterogeneity

High Content Screening to Find Best
Anti-Cancer Drugs

Single Cell RNA Sequencing Reveals the Heterogeneity of The Tumor and can Inform Treatment & Prognosis

Precision Medicine For Oncology in SA

Major aims: stage 2

Markers of disease identified in stage 1 will be used to develop
knowledge-driven, marker-specific, innovative diagnostic and therapeutic
approaches:

Proteomics, transcriptomics and metabolomics-based approaches to confirm validity of markers identified

Identification of substrates (small molecules, RNAi, proteins) interacting with key components of signal transduction pathways tightly associated with the markers identified

Generation and preclinical validation of disease-specific targeted combination products

In vivo animal studies using transgenic and humanized mouse models

Outlook: Integrating Various Immunotherapies

Immunotherapy is the treatment of cancer or inflammatory/autoimmune disease by inducing, enhancing or suppressing an immune response. Immunotherapy can be nonspecific or (antigen)-specific.

Nonspecific immunotherapy aims to enhance the overall host immune response

Specific immunotherapy targets the immune system against a particular tumor or increases tolerance towards a specific allergen.

There are four main categories of specific immunotherapy: adoptive immunotherapy, antibody-based immunotherapy, cancer vaccine therapy and allergen-specific immunotherapy. From these, adoptive and antibody-based immunotherapies are passive approaches, whereas cancer vaccine therapy and allergen-specific immunotherapy are active approaches.

Implementing Precision Medicine in Oncology in SA

Acknowledgments

Mhlanga Lab
Gene Expression & Biophysics Group
Univ. Cape Town Faculty of Medical Sciences
& CSIR - Pretoria
Laboratory of Prof. Stefan Barth
South African Research Chair in Cancer Biotechnology
Univ. Cape Town Faculty of Medical Sciences