Moffitt Cancer Center PS-OP: Bone Ecosystem Effects on Metastatic Prostate Cancer Evolution

Defining Bone Ecosystem Effects on Metastatic Prostate Cancer Evolution and Treatment Response Using an Integrated Mathematical Modeling Approach

Bone metastatic prostate cancer (mPCa) is currently an incurable disease. While standard of care treatments (androgen deprivation therapy (ADT), chemotherapy) are initially effective, this heterogeneous disease often evolves to become resistant. Thus, it represents a major clinical challenge.

PS-OP investigators also demonstrate that the bone ecosystem contributes to the emergence of resistant mPCa. However, how the ecosystem in turn, impacts the efficacy of standard of care treatment represents a major knowledge gap.

Biology driven mathematical models offer a novel and effective means with which to address these complex issues, since cancer evolution and bone ecosystem responses to applied therapies can be rapidly tested, optimized for efficacy to delay the onset of resistant disease, and subsequently, validated experimentally.

Using empirical data, the PS-OP is generating an agent-based mathematical model to describe the interactions of heterogeneous mPCa cells with the surrounding bone microenvironment. In silico, PS-OP investigators are testing the effect of standard of care treatments (i.e., ADT and chemotherapy) on the growth of cancer over time. The model can identify the impact of these treatments on mPCa cells but also the role of other bone cell types such as, mesenchymal stromal cells (MSCs) in disease progression.

Based on this rationale, the PS-OP hypothesizes that experimentally powered hybrid cellular automatons (HCAs) can be used to dissect the bone ecosystem effects on mPCa evolution and optimize treatment strategies so as to prevent the emergence of resistant disease. PS-OP researchers are testing this hypothesis through three aims:

• Examine the response of a HCA agent-based mathematical model of heterogeneous mPCa in bone to standard of care therapy, and validate the results in vivo.
• Explore the role of the bone ecosystem in controlling the emergence of resistance to standard of care treatments.
• Use evolutionary algorithms to guide the adaptive application of standard of care therapy.

These innovative PS-OP studies will generate a robust mathematical eco-evolutionary model of bone mPCa that can be used to dissect the role of the bone microenvironment in the emergence of resistance, identify the effects of standard of care therapies on heterogeneous cancer cells and the bone ecosystem and allow for the rapid determination of optimized adaptive therapies that take into account the contributions of the bone ecosystem.

The studies will ultimately significantly impact the way treatments are applied to patients diagnosed with bone mPCa.

Investigators

Conor C. Lynch, Ph.D.
Moffitt Cancer Center

Dr. Conor C. Lynch is currently an Associate Member/Professor in the Tumor Biology Department at the Moffitt Cancer Center. His primary research interest focuses on skeletal malignancies including metastatic prostate cancer. The majority of men that succumb to prostate cancer will have evidence of bone metastatic castrate resistant disease.

In collaboration with the clinicians and modelers in Genitourinary Oncology and the Integrated Mathematical Oncology Department at the Moffitt Cancer Center, his interdisciplinary team is focused on identifying the molecular mechanisms governing cancer-bone cross talk. To this end, his lab incorporates a number of pre-clinical animal models that recapitulate the pathophysiology of human prostate to bone metastasis and has extensive experience in bone imaging and in bone histology/histomorphometry. disease.

David Basanta, Ph.D.
Moffitt Cancer Center

Dr. David Basanta is an Associate Member/Professor at the Integrated Mathematical Oncology department at the Moffitt Cancer Center. His research focus on the ecological and evolutionary dynamics that drive cancer progression and the emergence of treatment resistance.

Together with the Lynch lab, Dr. Basanta and colleagues have developed integrated mathematical models that incorporate key players and molecules involved in bone homeostasis, this capturing the basic elements of bone ecology. This platform that can be used to study how bone metastatic prostate cancer cells can take advantage of the bone environment to grow and evolve. Importantly, it will allow us to understand how different prostate cancer cell phenotypes are selected for under a number of bone environments and thus help us understand the evolutionary dynamics that govern the tumor.