Pancreatic ductal adenocarcinomas respond poorly to standard treatments. Researchers at The University of Texas MD Anderson Cancer Center are applying the principles of physics to characterize the tumors, and these analyses could lead to individualized therapy.
The relatively new discipline of transport oncophysics describes how the physical properties of individual tumors affect the transport of chemotherapy drugs to cancer cells.
For example, gemcitabine must be able to cross vascular, extracellular, cellular, and molecular compartments to be effective. In some solid tumors, such as pancreatic ductal adenocarcinoma, certain physical characteristics in these transport mechanisms contribute to resistance to treatment.
“Onkos, the Greek root word for oncology, means mass,” said Eugene Koay, M.D., Ph.D., an assistant professor in the Division of Radiation Oncology. “The ancients knew that tumors have different physical properties than normal tissue, and recently, oncologists have been returning to the idea that these physical properties are a reflection of the underlying biology of tumors and may give us insight into patients’ prognosis and likelihood of response to specific treatments.”
Physical properties and barriers to treatment
About 80% of patients who have pancreatic ductal adenocarcinoma present with nonresectable disease, which is usually treated with chemotherapy drugs such as gemcitabine. But the response rates have been dismal, in part because physical barriers in the tumors prevent the effective delivery of gemcitabine and other cytotoxic chemotherapy drugs.
Unfortunately, biomarkers to predict response to specific treatments for pancreatic ductal adenocarcinoma are lacking. The only currently available biomarker is the serum CA19-9 level; an elevated level is associated with shorter survival. But testing for serum CA19-9 has several limitations, including poor sensitivity, false-negative results in patients who have the recessive allele for both types of Lewis antigens, and false-positive results in patients with obstructive jaundice.
Quantitative imaging assessment of transport properties
Transport oncophysics could help provide new biomarkers based on the physical characteristics of pancreatic ductal adenocarcinoma. Toward that end, Dr. Koay and his collaborators developed a mathematical model to measure mass transport properties using routine pancreatic-protocol, contrast-enhanced computed tomography (CT) scans of patients with pancreatic ductal adenocarcinoma. Researchers can use the mathematical model to track the changes in contrast enhancement of both normal tissue and cancer tissue between the phases of the CT scans.
Specifically, the model accounts for the variable density in tissue as a function of time; that is, changes in tissue density are measured by the transfer of contrast agent molecules through the vessel walls at certain rates and by rates of clearance from the vasculature. These calculations allow researchers to gain insight into the density of tumors’ stroma and vessels.
Dr. Koay and his colleagues used this quantitative technique in a clinical trial of intraoperative gemcitabine infusion in 12 patients with pancreatic ductal adenocarcinoma. Quantitative analysis of contrast-enhanced CT scans taken prior to surgery revealed a negative correlation between the degree of contrast enhancement in the tumors and gemcitabine delivery. The correlation is negative, Dr. Koay explained, because a high degree of enhancement indicates dense stroma, which impedes drug transport.
To further explore the relationship between CT findings and treatment outcomes, Dr. Koay and his colleagues retrospectively evaluated pretreatment contrast-enhanced CT scans of 110 patients who were treated with chemoradiation for pancreatic ductal adenocarcinoma in two clinical trials. The degree of enhancement on the CT scans was associated with pathological response to chemoradiation and overall survival, indicating that the transport properties of pancreatic tumors could be used as a biomarker. This information could be useful for therapeutic strategies aimed at the stroma and vasculature of pancreatic ductal adenocarcinomas.
Pancreatic ductal adenocarcinomas characteristically have dense stroma. Dr. Koay said, “The role of the dense stroma is complex. The stroma appears to partially impair pancreatic cancer cells from spreading to other organs, but it also serves as a barrier between chemotherapy and the tumor cells.” He also noted that the amount of stroma varies from patient to patient and from region to region within an individual tumor.
Variations in stromal density indicate a need to individualize therapeutic strategies that target the tumor stroma. Previous animal model studies of pancreatic cancer showed that depleting the stroma with agents that inhibit the hedgehog signaling pathway helped chemotherapy delivery, but patients treated with this stromal depletion strategy in a clinical trial had poorer survival outcomes than did patients treated with gemcitabine alone. However, this trial did not stratify patients by stromal density.
Quantitative imaging assessment of transport oncophysics could address the need for stratification in clinical trials and thus help to identify the patients most likely to benefit from certain treatment strategies. For example, in the intraoperative gemcitabine infusion trial, Dr. Koay’s group found that gemcitabine uptake had both a negative correlation with the density of the tumor stroma and a positive correlation with the uptake of human equilibrative nucleoside transporter 1 (hENT1), the primary transport protein that allows chemotherapy agents to enter the cellular compartment.
Pancreatic ductal adenocarcinoma is also characterized by an extensive desmoplastic response resulting in large stromal cells and abundant hyaluronic acid. Hyaluronic acid traps water, leading to high interstitial fluid pressure in the tumor stroma. This pressure becomes a barrier to effective chemotherapy delivery.
Investigators at other institutions are currently investigating whether enzymatic degradation of hyaluronic acid in pancreatic ductal adenocarcinoma can reduce interstitial pressure and improve chemotherapy delivery. Using quantitative imaging assessment to identify differences in stromal amount and composition could help identify patients who are most likely to benefit from this strategy. This is the subject of ongoing investigations in Dr. Koay’s laboratory.
Pancreatic ductal adenocarcinoma is also characterized by hypovascularity and resistance to radiation therapy. The resistance may result from multiple factors, including the relative hypoxia of the tumor, high interstitial fluid pressure, and intrinsic radioresistance of the tumor cells. Radiation itself induces the expression of vascular endothelial growth factor (VEGF), which contributes to hypoxia and thus may increase resistance to future radiation treatments.
Previous clinical trials at MD Anderson have attempted to use the VEGF inhibitor bevacizumab to sensitize pancreatic ductal adenocarcinoma to radiation therapy. Although most patients did not benefit from the addition of bevacizumab, several survived beyond 2 years. Patients in these trials were not stratified according to angiogenesis markers, but Dr. Koay hypothesizes that the patients who benefited from bevacizumab had denser microvasculature than the patients who did not benefit. Quantitative imaging assessment of vessel density could help identify the patients who might benefit from bevacizumab or other angiogenesis inhibitors, reinvigorating a “failed” treatment strategy for this disease for a subset of patients.
Most of Dr. Koay’s previous studies of quantitative imaging assessment were retrospective, and he is currently validating quantitative imaging assessment prospectively as the principal investigator of a clinical trial at MD Anderson (PA14-0319 or NCT02361320). The trial is recruiting patients with unresectable or borderline resectable pancreatic cancer, and Dr. Koay hopes to have results within 2 years.
Dr. Koay is also working with large cooperative groups such as the Alliance for Clinical Trials in Oncology, SWOG, and NRG Oncology to integrate his methods into ongoing clinical trials. Quantitative imaging assessment of pancreatic tumors’ transport properties can provide insight before treatment begins, and this assessment does not add health care costs because CT scans are part of the routine work-up for this disease. Indeed, Dr. Koay’s work has been incorporated into the MD Anderson Moon Shot programs for pancreatic, colorectal, and lung cancers.
In addition to improving treatment planning, transport oncophysics may further the understanding of clinically relevant processes such as tumorigenesis and metastasis. “This is an exciting time for oncology and the concept of transport oncophysics,” Dr. Koay said. “Physicists and physicians are communicating and acknowledging that cancer is both biologically and physically different than healthy tissue, and the National Institutes of Health is supporting the use of the physical sciences to understand cancer. If we could combine quantitative imaging assessments with traditional biomarkers, we could rationally direct therapeutic strategies for patients and improve their outcomes.”
For more information, contact Dr. Eugene Koay at firstname.lastname@example.org.
Koay EJ, Amer AM, Baio FE, et al. Toward stratification of patients with pancreatic cancer: Past lessons from traditional approaches and future applications with physical biomarkers. Cancer Lett. 2016. doi: 10.1016/j.canlet. 2015.12.006. [Epub ahead of print]
Koay EJ, Truty MJ, Cristini V, et al. Transport properties of pancreatic cancer describe gemcitabine delivery and response. J Clin Invest. 2014; 124:1525–1536.
OncoLog, September 2016, Volume 61, Number 9