Patient-Derived Xenograft (PDX) models are useful preclinical models for developing anti-cancer drugs employed in PDX clinical and co-clinical trials. PDX clinical trials, such as “phase II type clinical trial like mouse models”, can be used for the development of anti-cancer drugs before human clinical trials, with their efficacy assessed by the modified response evaluation criteria in solid tumors (mRECIST). Furthermore, co-clinical trials can be used for personalized care or precision medicine with the evaluation of a new drug or a novel combination. Cancer has remained one of the biggest challenges for human health during the past few decades despite major advances in medicine. High heterogeneity is a tumour characteristic and different types of cancer usually vary in clinical features and tumorigenic mechanisms, which results in different responses to drugs. Cancer cell lines and PDX models are widely used as preclinical tumour models for screening drugs and assessing drug responses. Cancer cell lines are derived from primary patient tumours and have contributed greatly to cancer research. Cancer cell lines are able to expand rapidly and are often used for high-throughput drug screening. Moreover, they are amenable to genetic modification, which is necessary for research on the mechanisms of cancer development. However, it is clear that histological and genetic features in cancer cell lines have changed a lot compared with those in native tumours. As a result, many drugs that perform well in cancer cell lines finally fail in clinical trials. PDX models are generated by transplanting fresh tumour tissue from patients subcutaneously or orthotopically into immunodeficient mice. They mimic the biological characteristics of the primary tumours better than cancer cell lines.

Conventional anti-cancer drugs can directly kill rapidly proliferating cells, while small molecule inhibitors and therapeutic antibodies can inhibit the intracellular growth signal cascade and lead to cancer cell-specific death. For the development of anti-cancer drugs, in vitro cell killing assays using commercially available patient-derived cell lines or in vivo tumour growth inhibition assays using cell-line-derived xenograft (CDX) models are commonly employed to measure the efficacy of drugs and to make a “go or no-go” decision for a further clinical study. Unfortunately, few drugs are approved even if the drugs demonstrate a good response in preclinical studies. Indeed, only 5% of the anti-cancer drugs that have anti-cancer activity in preclinical studies are approved for clinical application by the United States Food and Drug Administration (FDA).

To develop anti-cancer drugs for solid tumours, knowledge of the hallmarks of cancer and the cancer microenvironments is important. The cancer microenvironments consist of cancer cells and the surrounding cancer stromal cells. These stromal cells, including tumour endothelial cells (TECs), cancer-associated fibroblasts (CAFs), and tumour-associated macrophages (TAMs), are educated and activated by growth factors produced from cancer cells and promote cancer progression and metastasis. Additionally, the cancer stromal cells produce a collagen-rich extracellular matrix (ECM), which can interrupt drug distribution in the cancer tissue. Thus, knowledge of the cancer stroma is important for the development of drugs targeting solid tumours.

Traditional CDX models consist of many cancer cells but few cancer stromal cells, and they are difficult to use in preclinical models for predicting the response in clinical trials. This prompted attempts to inject patient-derived cancer tissue into immunodeficient mice, which has been conducted for over 40 years. These patient-derived xenograft (PDX) models conserve the original tissue’s biological features (histological architecture, especially cancer stroma construction, and gene expression or mutation status). A significant association was observed between drug responses in patients and the corresponding PDX models in 87% (112/129) of therapeutic outcomes. Thus, PDX models are recognized as accurate and clinically relevant models.

Rationale:

This study is being done to collect and store prostate cancer tissues and patient-matched normal tissue when available and blood for current and future cancer research studies in collaboration with Mayo Clinic. The tissues are waste tissues left over after diagnosis from biopsies. The IRB-approved protocol consents patients undergoing biopsies removal for prostate cancer and collects patient-matched diseased tissue and normal tissue along with blood.

This study is designed, using the tissues collected, to develop preclinical models i.e., cell lines and patient-derived tumour xenografts (PDTX) —patient tumours implanted into immune-deficient mice.

Objectives:

Two objectives are proposed for this project:

Aim 1. To collect cancer tissue to develop Nigerian patient preclinical models that include cell lines and patient-derived tumour xenografts (PDTX) that will be used for molecular characterization and testing novel therapies in these preclinical models to bridge the healthcare disparity gap in African patients with cancer. Molecular characterization may include short tandem DNA repeat; STR) and oncogenic/tumour suppressor gene mutation analyses to assure that the derived models have not been cross-contaminated during the development process with other ongoing lines. Tissue microarray and immunohistochemical (IHC) analysis will also be performed on cell lines, PDX and patient tissues to identify potential molecular targets for therapy.

Aim 2. For patients who consented, clinical therapy response data may be correlated with preclinical response data in cell lines and PDX models. Clinical data will include age, sex, race, histology, tumor stage, and treatment regimen with the response. Patient identifiers can be removed once clinical data is linked to preclinical data.