Biology subjects

Molkentine, J. M.

Publications and source records attributed to Molkentine, J. M..

3 recordsLinked to original sources

bioRxiv2021

Stromal HIF2 Regulates Immune Suppression in the Pancreatic Cancer Microenvironment

Background & AimsPancreatic ductal adenocarcinoma (PDAC) has a hypoxic, immunosuppressive stroma, which contributes to its resistance to immune checkpoint blockade therapies. The hypoxia-inducible factors (HIFs) mediate the cellular response to hypoxia, but their role within the PDAC tumor microenvironment remains unknown. MethodsWe used a dual recombinase mouse model to delete Hif1 or Hif2 in -smooth muscle actin (SMA)-expressing cancer-associated fibroblasts (CAFs) arising within spontaneous pancreatic tumors. The effects of CAF-Hif2 expression on tumor progression and composition of the tumor microenvironment were evaluated by Kaplan-Meier analysis, quantitative real-time polymerase chain reaction, histology, immunostaining, and by both bulk and single-cell RNA sequencing. CAF-macrophage crosstalk was modeled ex vivo using conditioned media from CAFs after treatment with hypoxia and PT2399, a HIF2 inhibitor currently in clinical trials. Syngeneic flank and orthotopic PDAC models were used to assess whether HIF2 inhibition improves response to immune checkpoint blockade. ResultsCAF-specific deletion of HIF2, but not HIF1, suppressed PDAC tumor progression and growth, and improved survival of mice by 50% (n = 21-23 mice/group, Log-rank P = 0.0009). Deletion of CAF-HIF2 modestly reduced tumor fibrosis and significantly decreased the intratumoral recruitment of immunosuppressive M2 macrophages and regulatory T cells. Treatment with the clinical HIF2 inhibitor PT2399 significantly reduced in vitro macrophage chemotaxis and M2 polarization, and improved tumor responses to immunotherapy in both syngeneic PDAC mouse models. ConclusionsTogether, these data suggest that stromal HIF2 is an essential component of PDAC pathobiology and is a druggable therapeutic target that could relieve tumor microenvironment immunosuppression and enhance immune responses in this disease.

cancer biology↗

bioRxiv2018

Enteral Activation of WR-2721 Mediates Radioprotection and Improved Survival from Lethal Fractionated Radiation

Unresectable pancreatic cancer is almost universally lethal because chemotherapy and radiation cannot completely stop the growth of the cancer. The major problem with using radiation to approximate surgery in unresectable disease is that the radiation dose required to ablate pancreatic cancer exceeds the tolerance of the nearby duodenum. WR-2721, also known as amifostine, is a well-known radioprotector, but has significant clinical toxicities when given systemically. WR-2721 is a prodrug and is converted to its active metabolite, WR-1065, by alkaline phosphatases in normal tissues. The small intestine is highly enriched in these activating enzymes, and thus we reasoned that oral administration of WR-2721 just before radiation would result in localized production of the radioprotective WR-1065 in the small intestine, providing protective benefits without the significant systemic side effects. Here, we show that oral WR-2721 is as effective as intraperitoneal WR-2721 in promoting survival of intestinal crypt clonogens after morbid irradiation. Furthermore, oral WR-2721 confers full radioprotection and survival after lethal upper abdominal irradiation of 12.5Gy x 5 fractions (total of 62.5Gy, D2EQ=140.6Gy), which would likely ablate pancreatic cancer. We find that the efficacy of oral WR-2721 stems from its selective accumulation in the intestine, but not in tumors or other normal tissues, as determined by in vivo mass spectrometry analysis. Thus, we demonstrate that oral WR-2721 is a well-tolerated, and quantitatively selective, radioprotector of the intestinal tract that is capable of enabling clinically relevant ablative doses of radiation to the upper abdomen without unacceptable gastrointestinal toxicity.

cancer biology↗

bioRxiv2017

EGLN Inhibition Reduces Gastrointestinal Radiation Toxicity and Improves Survival in a Murine Model of Locally Advanced Pancreatic Cancer

Locally advanced pancreatic cancer (LAPC) almost always fatal since it is unresectable and chemotherapy is only modestly effective. The efficacy of radiation therapy (RT) for LAPC is limited by the potentially fatal toxicity to nearby intestines. There are no FDA-approved medications that can prevent this radiotoxicity, but we find that FG-4592, a small molecule inhibitor of EGLN proteins, significantly reduces radiation damage to the intestines without radioprotecting tumors. KPC (KrasLSL/+; Trp53FL/+; Ptf1aCre/+) animals received dose-escalated radiation treatments with and without FG-4592 for radioprotection. High-dose RT reduced death from local progression, improved survival, and shifted the patterns of failure to a late metastatic death compared to controls. The addition of FG-4592 to RT further improved survival compared to vehicle controls by eliminating radiation-induced gastrointestinal toxicity. Thus, selective protection of the intestinal tract by EGLN inhibition may enable higher, and potentially definitive doses of cytotoxic therapy to be delivered to LAPC.\n\nOne Sentence SummaryThe EGLN inhibitor FG-4592 allows higher, and potentially definitive, doses of radiation to be delivered to pancreatic cancer by reducing normal tissue toxicity without protecting tumors.

cancer biology↗