Surrogate biomarkers for assessing changes in pancreatic cancer tumor microenvironment

Abstract public domain (NIH RePORTER)

Pancreatic ductal adenocarcinoma (PDAC) is lethal, with a 5-year survival rate of less than 10%. Radical surgical resection is the only curative option; however, few pancreatic cancer patients have resectable disease at diagnosis. For a subset of patients with borderline resectable tumors, neoadjuvant therapies can downstage the disease and enable surgical resection. Protumor characteristics (i.e., hypoxia, high stromal density, high tissue pressure, and a high number of immunosuppressive cells) reduce the efficacy of neoadjuvant therapies. Stereotactic body radiation therapy (SBRT) is more effective than traditional radiation therapy for downstaging PDAC, but not all tumors are responsive. Traditionally, tumor treatment response is evaluated using anatomical tumor measurements, but this is limited because tumor size often does not correlate with tumor response. To improve this situation, we will establish a fundamentally new tool to image PDAC tumors to augment the available diagnostic imaging. We will advance shear modulus (SM) and vascular perfusion (VP) as surrogate imaging biomarkers for assessing tumor response to neoadjuvant therapies. In a uniquely beneficial approach for a difficult tumor to characterize, this project will combine pre-surgical, intra-surgical, and post-resection imaging with in vivo perfusion assessment and ex vivo pathology. Our extensive pre-clinical results demonstrate that SM and VP are sensitive to changes in protumor characteristics. Therefore, we hypothesize that SM and VP changes are direct diagnostics of the tumor microenvironment and can be used to assess therapeutic efficacy and response. To test this, we will combine shear wave elastography (SWE) with optical fluorescence tomography (OFT) of indocyanine green optical tissue perfusion tracer to evaluate the interplay between SM and Gemcitabine perfusion for different therapies, providing more comprehensive information regarding tumor response. We will develop a new hybrid imaging tool to systematically assess how SM and VP vary during neoadjuvant therapies through two specific aims: In Aim 1, we will perform pre-clinical studies with three progressive PDAC murine models that have different features that recapitulate human disease to evaluate how SM and VP relate to (a) stromal density, (b) the number of immunosupportive cells, and (c) the degree of hypoxia during SBRT, chemotherapy, and chemoradiation therapy. In Aim 2, we will clinically translate this work. We will compare our interventional SWE and OFT imaging to magnetic resonance elastography (MRE) and dynamic-contrast-enhanced magnetic resonance imaging to assess tumor microenvironmental changes during SBRT, chemotherapy, and chemoradiation therapy. We will also perform SWE on excised PDAC to evaluate how SM and VP relates to tumor microenvironment changes. These new imaging features are potential surrogate biomarkers, enabling clinicians to recognize whether treatment succeeds or fails. This practice-changing information will allow for the optimization of neoadjuvant treatment protocols on an individualized patient basis, resulting in more curative surgical candidates.

Public health relevance public domain (NIH RePORTER)

Surgical resection is the only curative therapy for patients with pancreatic ductal adenocarcinoma. However, only 15-20% of pancreatic cancer patients have resectable disease at diagnosis. For patients with borderline resectable tumors, targeted neoadjuvant therapies can downstage the tumor and enable surgical resection; however, these therapies would be more useful if clinicians had real-time information regarding patient response. To inform therapeutic decisions, we plan to establish shear modulus and vascular perfusion as imaging biomarkers for assessing patient response to neoadjuvant therapy, which should improve the treatment of pancreatic cancer patients.