Dynamic changes during the treatment of pancreatic cancer

Abstract

This manuscript follows a single patient with pancreatic adenocarcinoma for a five year period, detailing the clinical record, pathology, the dynamic evolution of molecular and cellular alterations as well as the responses to treatments with chemotherapies, targeted therapies and immunotherapies. DNA and RNA samples from biopsies and blood identified a dynamic set of changes in allelic imbalances and copy number variations in response to therapies. Organoid cultures established from biopsies over time were employed for extensive drug testing to determine if this approach was feasible for treatments. When an unusual drug response was detected, an extensive RNA sequencing analysis was employed to establish novel mechanisms of action of this drug. Organoid cell cultures were employed to identify possible antigens associated with the tumor and the patient’s T-cells were expanded against one of these antigens. Similar and identical T-cell receptor sequences were observed in the initial biopsy and the expanded T-cell population. Immunotherapy treatment failed to shrink the tumor, which had undergone an epithelial to mesenchymal transition prior to therapy. A warm autopsy of the metastatic lung tumor permitted an extensive analysis of tumor heterogeneity over five years of treatment and surgery. This detailed analysis of the clinical descriptions, imaging, pathology, molecular and cellular evolution of the tumors, treatments, and responses to chemotherapy, targeted therapies, and immunotherapies, as well as attempts at the development of personalized medical treatments for a single patient should provide a valuable guide to future directions in cancer treatment.

Vestigial-like 1 is a shared targetable cancer-placenta antigen expressed by pancreatic and basal-like breast cancers

“…Patient MP015 was first diagnosed with primary PDAC in December 2011. As previously reported, two years following surgical removal of the primary pancreatic tumor, a thorascopic wedge resection of a left lung lesion was performed in November 2013 and used to derive organoid cell line MP015-Org 33 . The patient’s disease was kept in check for nearly 2 more years through a series of chemotherapeutic regimens, but following progression, he was enrolled in a cell therapy protocol approved by the M.D.…”

“…Although the patient experienced a transient fever (a frequent side effect of T-cell-infusion-induced cytokine release), they experienced no adverse events indicating potential CTL-mediated toxicities. Unfortunately, scans in late November 2015 showed rapid disease progression manifested as an interval increase in lung lesions and pleural-based metastatic disease 33 . Surprisingly, a biopsy of a pleural-based nodule taken at this time revealed a poorly differentiated neuroendocrine tumor.…”

“…With the exception of a mammary cell line, VGLL1 CTLs did not recognize most HLA-A*0101-expressing matched normal primary cells. Patient infusion of autologous VGLL1 CTLs resulted in no autoimmune toxicities but also failed to induce a clinical response, likely due to VGLL1 antigen loss by the metastatic tumor 33 . Comparative gene expression profiling revealed that VGLL1 is a member of a unique group of cancer-placenta antigens (CPA) that demonstrate high expression in placenta, low to absent expression in essential normal tissues, and overexpression in several different cancers.…”

Optical Metabolic Imaging of Heterogeneous Drug Response in Pancreatic Cancer Patient Organoids

“…Pancreatic organoids can be used for drug screens directly on patient cells, which could enable rational treatment planning for individual patients (7)(8)(9). Organoids also provide a platform to discover new drugs and drug combinations to treat pancreatic cancer patients, who currently suffer from a severe lack of effective treatment options.…”

“…Most pancreatic tumors do not express a specific therapeutic target (6), and the driver mutations present in a patient's cancer do not predict their response to chemotherapy. Alternatively, pancreatic organoids have emerged as an appealing method to tailor treatments by performing high-throughput drug screening directly on a patient's tumor cells (7)(8)(9). In vitro organoids recapitulate the genetic and histopathological characteristics of the original pancreatic tumor, along with its complex 3-dimensional organization (10)(11)(12)(13)(14).…”