Select Research Initiatives of the BDP
Learn about some of our research initiatives, which are advancing the development of biomarkers for several different types of cancer.
Intervention in Early-Stage Cancer: Liquid Biopsies to Detect Minimal Residual Disease
Circulating tumor DNA (ctDNA) obtained from plasma during a routine blood draw, a technique known as “liquid biopsy,” can be used to detect molecular minimal residual disease (MRD) and may reliably identify patients with certain types of cancer who are at high risk for recurrence.
The central hypothesis of this protocol is that after patients with breast cancer, lung cancer, and other solid tumors have received curative-intent therapy, serial ctDNA testing using a highly sensitive and specific MRD assay can identify patients with evidence of MRD. This identification provides an opportunity for early intervention that potentially can improve the cure rate in these patients.
This protocol aims to:
- Develop and optimize a tumor-informed ctDNA assay for early detection of MRD.
- Determine the rate of MRD positivity based on detection of ctDNA in plasma following curative-intent therapies (such as surgery, chemotherapy before or after surgery, and radiation therapy).
- Determine the prognostic significance of ctDNA monitoring for MRD detection following curative-intent therapies.
- Determine the lead time between ctDNA positivity in the plasma and clinical detection of metastatic disease.
Disease Monitoring: Guiding Treatment Decisions in Advanced-Stage Cancer
Biomarker development is critical to optimally inform medical decision-making for all aspects of disease management. The current biomarker landscape for prostate cancer is evolving rapidly. An ever-increasing number of publications has reported varying degrees of association between the result from a biomarker assay and clinical outcome. However, few of the assays reported have undergone sufficient analytical validation prior to clinical testing. Additionally, many clinical validation studies are retrospective and include patients that were managed differently with respect to the laboratory and imaging tests used to assess disease status and the frequency at which they were performed. All these things limit the strength and reliability of the associations.
This new program is focused is on post-treatment pharmacodynamic response and disease-monitoring biomarkers, both of which require pre- and post-intervention sampling. Evaluating these biomarkers within a program integrated with imaging from patients is incredibly complex and not standardized in the field of research. The BDP is paving the way by developing a platform that can be used across cancer types.
One of the first collaborations using this protocol involves a platform that allows simultaneous analysis of both circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) or cell-free DNA (cfDNA). Principal Investigator Howard Scher hypothesizes that longitudinal assessment of both CTCs and cf/ctDNA will aid current imaging and biochemical tools in monitoring patients with advanced prostate cancer. The goal of studies under this program is to generate the evidence to support the clinical validity and utility of CTC and cf/ctDNA biomarkers in the context of tools that are currently available to assess prostate cancer.
Technological Innovation: Initial Validation of Novel Biomarker Assays
The BDP is involved in numerous concurrent studies related to the clinical validation of emerging technologies. These technologies use various liquid biopsies, including but not limited to circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and cell-free DNA (cfDNA). One example project is outlined below:
Clinical Validation of Circulating Tumor Cells (CTCs) Isolation to Increase Blood-Based Cancer Detection Rates in Patients With Advanced Non-Small Cell Lung Cancer
The comprehensive molecular analysis of lung cancers is an essential part of patient management for guiding precision therapy. However, tissue biopsies to obtain tumor material are often challenging, and failure rates of sequencing these biopsy samples are high. Noninvasive blood-based testing methods such as cell-free DNA (cfDNA) have the potential to address this unmet need. However, current assay detection is unsuccessful in many patients with advanced lung cancers.
Circulating tumor cells (CTCs) have potential to address these shortcomings, but the majority of studies with CTCs have focused on understanding prognosis and disease monitoring. As part of this protocol, we propose to use CTCs as a diagnostic tool to increase cancer detection rates. We hypothesize that it is important to study CTCs at the single-cell level, especially in patients with metastatic disease, to gain early insights into the mechanisms of disease resistance before they clinically manifest. This will potentially enable early intervention, while the burden of disease is minimal.
Molecular Insights: Developing Preclinical Models
Members of the BDP are focused on developing more accurate preclinical models for use in the lab, including patient-derived xenograft (PDX) mouse models.
Developing Organoid and Patient-Derived Xenograft (PDX) Models of Prostate Cancer Using Circulating Tumor Cells (CTCs) Captured With Microfluidics Devices
We will use a circulating tumor cell (CTC) microfluidics device that leverages the differences in the physical properties of CTCs to separate and capture live tumor cells from peripheral blood. The device has shown promise by our group in spiking experiments with recovery rates that exceed 90% for PC3 cell lines spiked into whole blood — mimicking the analysis of patient samples. Although the technology currently has not been evaluated in prostate cancer using patient-derived blood samples, studies in breast and pancreatic cancer have demonstrated successful isolation of CTCs. Moreover, a study evaluating the technology’s ability to generate patient-derived xenograft (PDX) mouse models from patients with pancreatic adenocarcinoma demonstrated an impressive 100% success rate.
CTC samples will be collected from patients who meet the study eligibility requirements. Organoid and PDX models will be developed from captured CTCs using established methodologies. Downstream analysis, including but not limited to next-generation sequencing (DNA and/or RNA) and time-course studies, will be used to determine the effects of drug exposure in tumor cells with specific genomic alterations and to understand the mechanisms underlying sensitivity and resistance to treatments.
This protocol aims to:
- Determine the overall rate of success of organoid and/or PDX model generation using CTCs from patients with metastatic prostate cancer that have been isolated using CTC microfluidics devices.
- Generate organoid and PDX models of various phenotypic and genomic subsets of metastatic prostate cancer.
- Compare the genotypic and phenotypic characteristics of CTC-derived organoids with those of the corresponding primary and metastatic tumor samples at tumor bulk and single-cell levels.
- Assess the therapeutic responses to standard care and/or novel therapeutic agents in CTC-derived organoids and compare these with patient outcomes.