Austin Pantel

[18F](2S,4R)4-Fluoroglutamine PET Detects Glutamine Pool Size Changes in Triple Negative Breast Cancer in Response to Glutaminase Inhibition

Glutaminolysis is a metabolic pathway adapted by many aggressive cancers, including triple-negative breast cancers (TNBC), to utilize glutamine for survival and growth. In this study, we examined the utility of [18F](2S,4R)4-fluoroglutamine ([18F]4F-Gln) PET to measure tumor cellular glutamine pool size, whose change might reveal the pharmacodynamic (PD) effect of drugs targeting this cancer-specific metabolic pathway. High glutaminase (GLS) activity in TNBC tumors resulted in low cellular glutamine pool size assayed via high-resolution 1H magnetic resonance spectroscopy (MRS). GLS inhibition significantly increased glutamine pool size in TNBC tumors. MCF-7 tumors, with inherently low GLS activity compared with TNBC, displayed a larger baseline glutamine pool size that did not change as much in response to GLS inhibition. The tumor-to-blood-activity ratios (T/B) obtained from [18F]4F-Gln PET images matched the distinct glutamine pool sizes of both tumor models at baseline. After a short course of GLS inhibitor treatment, the T/B values increased significantly in TNBC, but did not change in MCF-7 tumors. Across both tumor types and after GLS inhibitor or vehicle treatment, we observed a strong positive correlation between T/B values and tumor glutamine pool size measured using MRS (r2 = 0.71). In conclusion, [18F]4F-Gln PET tracked cellular glutamine pool size in breast cancers with differential GLS activity and detected increases in cellular glutamine pool size induced by GLS inhibitors. This study accomplished the first necessary step toward validating [18F]4F-Gln PET as a PD marker for GLS-targeting drugs. Cancer Res; 77(6); 1476-84. ©2017 AACR.

Molecular imaging to guide systemic cancer therapy: Illustrative examples of PET imaging cancer biomarkers

Molecular imaging agents have the ability to non-invasively visualize, characterize, and quantify the molecular biology of disease. Recent advances in nuclear probe development, particularly in PET radiotracers, have generated many new imaging agents with precise molecular targets. With such specificity, PET probes may be utilized as biomarkers to objectively interrogate and evaluate pathology. Whereas the current indications for PET imaging are predominately confined to staging and restaging of malignancy, the utility of PET greatly expands when utilized as a biomarker, the topic of this review. As an imaging biomarker, PET may be used to (1) measure target expression to select subsets of patients who would most benefit from targeted therapy; (2) measure early treatment response to predict therapeutic efficacy; and (3) relate tumor response to survival. This review will discuss the application of radiotracers to targeted cancer therapy. Particular attention is given to new radiotracers evaluated in recently completed clinical trials and those with current or potential clinical utility. The diverse roles of PET in clinical trails for drug development are also examined.

A PET imaging agent for evaluating PARP-1 expression in ovarian cancer

BACKGROUND. Poly(ADP-ribose) polymerase (PARP) inhibitors are effective in a broad population of patients with ovarian cancer; however, resistance caused by low enzyme expression of the drug target PARP-1 remains to be clinically evaluated in this context. We hypothesize that PARP-1 expression is variable in ovarian cancer and can be quantified in primary and metastatic disease using a novel PET imaging agent. METHODS. We used a translational approach to describe the significance of PET imaging of PARP-1 in ovarian cancer. First, we produced PARP1-KO ovarian cancer cell lines using CRISPR/Cas9 gene editing to test the loss of PARP-1 as a resistance mechanism to all clinically used PARP inhibitors. Next, we performed preclinical microPET imaging studies using ovarian cancer patient–derived xenografts in mouse models. Finally, in a phase I PET imaging clinical trial we explored PET imaging as a regional marker of PARP-1 expression in primary and metastatic disease through correlative tissue histology. RESULTS. We found that deletion of PARP1 causes resistance to all PARP inhibitors in vitro, and microPET imaging provides proof of concept as an approach to quantify PARP-1 in vivo. Clinically, we observed a spectrum of standard uptake values (SUVs) ranging from 2–12 for PARP-1 in tumors. In addition, we found a positive correlation between PET SUVs and fluorescent immunohistochemistry for PARP-1 (r2 = 0.60). CONCLUSION. This work confirms the translational potential of a PARP-1 PET imaging agent and supports future clinical trials to test PARP-1 expression as a method to stratify patients for PARP inhibitor therapy. TRIAL REGISTRATION. Clinicaltrials.gov NCT02637934. FUNDING. Research reported in this publication was supported by the Department of Defense OC160269, a Basser Center team science grant, NIH National Cancer Institute R01CA174904, a Department of Energy training grant DE-SC0012476, Abramson Cancer Center Radiation Oncology pilot grants, the Marsha Rivkin Foundation, Kaleidoscope of Hope Foundation, and Paul Calabresi K12 Career Development Award 5K12CA076931.

A phase I study of pazopanib in combination with escalating doses of 131I in patients with well-differentiated thyroid carcinoma borderline refractory to radioiodine

Objective This trial was conducted to evaluate the ability of pazopanib to overcome therapeutic 131I resistance. Materials, methods and patients This phase 1 trial assesses the combination of pazopanib and escalating doses of radioiodine (131I) in patients with recurrent or metastatic thyroid cancer that are borderline or relatively iodine refractory. Radioiodine uptake scans were assessed post therapy and compared to historical pre-treatment scans. Patients underwent FDG PET/CT before and after the initial pazopanib treatment to identify the impact of pazopanib on the cancer prior to 131I therapy. Results A dose limiting toxicity (cardiac arrhythmia and grade 3 fatigue) in the first patient in the first cohort prompted expansion to a total of 6 patients. Additional grade 3–4 hematologic toxicity and low accrual in the expanded cohort led to the decision not to pursue further study of the regimen. In patients with measurable disease 4/5 (80%) achieved stable disease. Median progression free survival was 6.7 months. At 3 years of follow up, one patient died due to progressive disease, two are being treated with systemic therapy and 3 continue without requiring subsequent therapy at 15, 27 and 35 months from the last dose of pazopanib. There was no convincing impact of pazopanib on iodine uptake in scans performed pre- and post-therapy compared to scans from historical 131I treatments without pazopanib. Conclusion Despite a suggestion of therapeutic efficacy, combined pazopanib and 131I resulted in increased toxicity. There was no convincing evidence that the administration of pazopanib improved iodine uptake or retention. Trial registration ClinicalTrials.gov NCT01413113

Imaging Cancer Metabolism: Underlying Biology and Emerging Strategies

Dysregulated cellular metabolism is a characteristic feature of malignancy that has been exploited for both imaging and targeted therapy. With regard to imaging, deranged glucose metabolism has been leveraged using 18F-FDG PET. Metabolic imaging with 18F-FDG, however, probes only the early steps of glycolysis; the complexities of metabolism beyond these early steps in this single pathway are not directly captured. New imaging technologies—both PET with novel radiotracers and MR-based methods—provide unique opportunities to investigate other aspects of cellular metabolism and expand the metabolic imaging armamentarium. This review will discuss the underlying biology of metabolic dysregulation in cancer, focusing on glucose, glutamine, and acetate metabolism. Novel imaging strategies will be discussed within this biologic framework, highlighting particular strengths and limitations of each technique. Emphasis is placed on the role that combining modalities will play in enabling multiparametric imaging to fully characterize tumor biology to better inform treatment.

Abstract A054: Real-time imaging of PARP-1 in ovarian cancer

Introduction: Poly(ADP-ribose) polymerase inhibitors (PARPi) are emerging targeted therapeutics for the treatment of ovarian cancer and were initially recognized to work in BRCA1/2 mutation carriers. However, a recent clinical trial showed that all platinum-sensitive ovarian cancer patients benefited from the second-generation PARPi, niraparib, suggesting newer biomarkers would be useful for patient selection. Second-generation PARPi are more effective at trapping PARP-1 on DNA lesions and have improved cellular lethality compared to first-generation PARPi. Due to the critical role of PARP-1 in the PARP trapping hypothesis, PARP-1 expression has the potential to serve as a biomarker for the appropriate selection of ovarian cancer patients for PARPi therapy. In this work, we present the noninvasive real-time imaging of PARP-1 through positron emission tomography (PET) with a radiolabeled PARPi, [18F]FluorThanatrace ([18F]FTT) in primary and disseminated ovarian cancer as a novel approach to quantify PARP-1 expression and monitor patients on PARP inhibitor therapy. Methods: Patients underwent [18F]FTT PET/CT imaging on a whole-body PET/CT scanner (Phillips Medical System, Netherlands). Image reconstruction was carried out using standard procedures. Images were interpreted by trained nuclear medicine physicians who first located lesions on a contemporaneous clinical [18F]FDG study and then found the corresponding lesion on the [18F]FTT image and recorded the maximum standard-uptake-value (SUV). Immunohistochemistry using clinical adjacent tumor sections was performed for hematoxylin and eosin (HE) and biomarkers including PARP-1, γH2AX, p-53, LCA, and AE1-3. Furthermore, PARP-1 was evaluated by both fluorescent IHC and [125I]KX1 autoradiography on adjacent sections and was correlated with maximum SUV of [18F]FTT for known sites of disease. Results: We enrolled 10 EOC patients, 7 of whom underwent [18F]FTT imaging in addition to standard clinical management including surgical debulking or biopsy. A total of 14 tissue specimens were available from the 10 patients and were used for in vitro assays including PARP-1 fluorescent IHC and [125I]KX1 autoradiography. We observed a spectrum of [18F]FTT uptake. Maximum SUV ranged from as low as 2 (background) to as high as 12.1. In addition, we found a correlation (r2 = 0.74, 0.79) between PARP-1 fluorescent IHC and [18F]FTT PET imaging, as well as with FTT analogue [125I]KX1 autoradiography. No correlations were found between PARP-1 fluorescent IHC or [18F]FTT and [18F]FDG. Conclusion: We found that uptake of [18F]FTT positively correlated with PARP-1 expression by fluorescent IHC. This provides early proof of concept of [18F]FTT as a clinical biomarker of PARP-1 expression in primary and disseminated disease. The spectrum of PARP-1 expression measured by [18F]FTT ranged from maximum SUV of 2 to 12, providing preliminary evidence for differences in PARP-1 expression affecting PARPi tumor targeting. Studies are now under way evaluating [18F]FTT as a biomarker to assess PARPi drug target engagement with the goal of entering multicenter clinical trials in ovarian, breast, and prostate cancer. Citation Format: Mehran Makvandi, Austin Pantel, Lauren Schwartz, Robert Doot, Fiona Simpkins, David A. Mankoff, Robert H. Mach, Lilie Lin. Real-time imaging of PARP-1 in ovarian cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A054.

Abstract AP20: A PILOT STUDY OF A POLY (ADP–RIBOSE) POLYMERASE–1 (PARP) TARGETED NOVEL PET TRACER (18F–FLUOURTHANOTRACE) IN PATIENTS WITH OVARIAN CARCINOMA

PURPOSE: There is now substantial data that poly (ADP-ribose) polymerase-1 (PARP) inhibitors have activity in tumors with defects in homologous recombination, in particular BRCA-related cancers. One of the challenges, however, is identifying patients that may best respond to these class of drugs. 18F-FTT (fluorthanotrace) is a novel PET imaging tracer that can quantify PARP enzyme activity in vivo. We report results on an initial pilot study of 18F-FTT imaging in patients with ovarian carcinoma. METHODS: Eight patients with newly diagnosed or recurrent ovarian, primary peritoneal, or fallopian tube carcinoma and measurable disease underwent both 18F-FDG PET/CT and 18F-FTT PET/CT imaging within 30 days of each other. Patients who were undergoing surgery or had disease amenable to biopsy underwent dynamic imaging of the abdomen/pelvis and static skull base to mid-thigh imaging following injection of approximately 10mCi of 18F-FTT. Patients with no biopsy accessible disease underwent a series of whole body PET/CT scans over 4 hours following injection of 18F-FTT to evaluate the biodistribution and dosimetry of 18F-FTT. Standardized uptake value (SUV) was calculated for primary and/or metastatic implants on all patients with quantifiable tumor on both PET/CT scans. Quantitative assessment of the 18F-FTT PET/CT was performed first using the 18F-FDG PET/CT to identify and match lesions. Regions of interest were then drawn over the tumor implant using multiple planar view. Up to three lesions were quantified on each dataset (primary and metastases if present). Ex vivo autoradiography with [ 125I]-KX (a novel radio-iodinated PARP radiotracer that can quantitatively assess PARP-1 enzyme expression in vitro), immunohistochemical staining with γh2ax, CD45, and keratin was performed on tumor samples. RESULTS: Active regions of disease was noted for 7/8 patients on 18F-FDG PET/CT imaging and 18F-FTT PET/CT imaging. Maximum SUV of primary or metastases on 18F-FDG PET/CT ranged from 1.97-14.54 and on 18F-FTT PET/CT ranged from 3.04-12.13. We acquired tumor tissue on four patients for analysis. SUV on 18F-FTT PET/CT correlated with average counts/area on [ 125I]-KX autoradiography (R=0.70) and gammh2ax immunohistochemistry staining on tumor specimens. Low SUV FTT:FDG ratio was noted in 4/4 patients with platinum resistant disease and/or low PARP-1 expression on [ 125I]-KX autoradiography and high FTT:FDG ratio was noted in 2/3 patients with platinum sensitivity and/or high binding on [ 125I] KX auto-radiography. CONCLUSION: Our initial preliminary studies demonstrate that 18F-FTT localizes to known areas of tumor and may distinguish between tumors with low level expression of PARP and platinum resistance vs high levels of PARP and platinum sensitivity and may be a promising biomarker for PARP inhibitor and platinum sensitivity. Citation Format: Lilie Lin MD, Mehran Makvandi PharmD, Austin Pantel MD, Robert Doot PhD, Lauren Schwartz MD, Fiona Simpkins MD, David Mankoff MD PHD, Robert Mach PhD. A PILOT STUDY OF A POLY (ADP–RIBOSE) POLYMERASE–1 (PARP) TARGETED NOVEL PET TRACER (18F–FLUOURTHANOTRACE) IN PATIENTS WITH OVARIAN CARCINOMA [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP20.