Spatially fractionated stereotactic body radiation therapy (Lattice) for large tumors

Purpose: Stereotactic body radiation therapy (SBRT) has demonstrated clinical benefits for patients with metastatic and/or unresectable cancer. Technical considerations of treatment delivery and nearby organs at risk can limit the use of SBRT in large tumors or those in unfavorable locations. Spatially fractionated radiation therapy (SFRT) may address this limitation because this technique can deliver high-dose radiation to discrete subvolume vertices inside a tumor target while restricting the remainder of the target to a safer lower dose. Indeed, SFRT, such as GRID, has been used to treat large tumors with reported dramatic tumor response and minimal side effects. Lattice is a modern approach to SFRT delivered with arc-based therapy, which may allow for safe, high-quality SBRT for large and/or deep tumors. Methods and Materials: Herein, we report the results of a dosimetry and quality assurance feasibility study of Lattice SBRT in 11 patients with 12 tumor targets, each ≥10 cm in an axial dimension. Prior computed tomography simulation scans were used to generate volumetric modulated arc therapy Lattice SBRT plans that were then delivered on clinically available Linacs. Quality assurance testing included external portal imaging device and ion chamber analyses. Results: All generated plans met the standard SBRT dose constraints, such as those from the American Association of Physicists in Medicine Task Group 101. Additionally, we provide a step-by-step approach to generate and deliver Lattice SBRT plans using commercially available treatment technology. Conclusions: Lattice SBRT is currently being tested in a prospective trial for patients with metastatic cancer who need palliation of large tumors (NCT04553471, NCT04133415)

Discovery and Characterization of Human Recombinant anti-uPAR antibodies

The urokinase plasminogen activator receptor (uPAR) is involved in the proliferation and migration of cells from diverse lineages. As a heavily glycosylated, glycosyl phosphotidyl inositol (GPI) linked protein of approximately 300 amino acids, its ubiquitousness in many aggressive cancer types-triple negative breast cancer (TNBC) in particular-makes it an attractive target for uPAR-directed therapies. uPAR participates in many protein/ protein interactions, which leads to pericellular proteolysis and "outside-in" signaling that is mediated by specific integrins. Here, the Craik Lab's human antigen-binding fragment (Fab) phage display library was panned for anti-uPAR antibodies. In total, 22 unique anti-uPAR Fabs were found. Two of these, 2G10 and 3C6, were found to antagonize the the uPAR/uPA and uPAR/β1 integrin interactions. While antagonism of these interactions did not effect cytotoxic responses, the antagonism did prevent uPAR over-expressing H1299 cells from migrating through a layer of cross-linked extracellular matrix. Further investigation revealed coarse-level binding sites of 2G10 and 3C6, as well as a unique feature of 3C6's ability to antagonize the uPAR/β1 integrin interaction by binding uPAR in an extended conformation. While surface plasmon resonance (SPR) revealed high binding affinities of 2G10 and 3C6 for uPAR, apparent affinities of 2G10 and 3C6 for the uPAR over-expressing MDA-MB-231 cells were different, and suggested that 3C6 Fab has a very poor affinity for uPAR. Regardless, both antibodies preferentially accumulated in MDA-MB-231-derived tumors, and demonstrated favorable pharmacokinetics and high tumor uptake. As a promising result, 2G10 IgG labeled with 177Lu demonstrated potent anti-tumor activity. The results of my research provide both reagents and a framework for the development of a multi-modal clinical probe and therapeutic for cancers, and other disorders, where uPAR over-expression plays a role

Quantitative assessment of PSMA PET response to therapy in castration-sensitive prostate cancer using an automated imaging platform for disease identification and measurement.

RationaleProstate cancer treatment response may be automatically quantified using a molecular imaging analysis platform targeting prostate-specific membrane antigen (PSMA).MethodsA retrospective analysis of patients with castration-sensitive prostate cancer who underwent PSMA-targeted molecular imaging prior to and 3 months or more after treatment was conducted. Disease burden was analyzed with aPROMISE, an artificial intelligence imaging platform that automatically quantifies PSMA-positive lesions. The calculated PSMA scores for prostate/bed, nodal, and osseous disease sites were compared with prostate-specific antigen (PSA) values.ResultsOf 30 eligible patients, the median decline in prostate/bed, nodal, and osseous disease PSMA scores were 100% (range 52-100%), 100% (range - 87-100%), and 100% (range - 21-100%), respectively. PSMA score decline was significantly associated with PSA decline.ConclusionChanges in aPROMISE PSMA scores are associated with changes in PSA and may quantify treatment response

HOXA5 Regulates hMLH1 Expression in Breast Cancer Cells

Homeobox protein HOXA5 functions as a transcriptional factor for genes that are not only involved in segmentation identity but also in cell differentiation. Although HOXA5 has been shown to regulate the expression of the tumor-suppressor protein p53, its role in breast tumorigenesis is not well understood. Using yeast as a model system, we now demonstrate that overexpression of HOXA5 in yeast can be used to identify downstream target genes that are homologous in humans. One such identified gene was that of the mismatch repair pathway component MutL homolog 1. Analysis of the promoter region of the gene for human MutL homolog 1 (hMLH1) displayed several putative HOXA5-binding sites. In transient transfection experiments, the overexpression of HOXA5 transactivated the hMLH1 promoter-reporter construct. In addition, chromatin immunoprecipitation assay using a human breast cancer cell line MCF-7 demonstrated that HOXA5 binds to the hMLH1 promoter in vivo. Furthermore, we demonstrate that, in the presence of HOXA5, there is an increase in in vivo repair activity in MCF-7 cells. Taken together, our results indicate that HOXA5 is a transcriptional regulator of hMLH1 in breast cancer cells

Imaging the urokinase plasminongen activator receptor in preclinical breast cancer models of acquired drug resistance.

Subtype-targeted therapies can have a dramatic impact on improving the quality and quantity of life for women suffering from breast cancer. Despite an initial therapeutic response, cancer recurrence and acquired drug-resistance are commonplace. Non-invasive imaging probes that identify drug-resistant lesions are urgently needed to aid in the development of novel drugs and the effective utilization of established therapies for breast cancer. The protease receptor urokinase plasminogen activator receptor (uPAR) is a target that can be exploited for non-invasive imaging. The expression of uPAR has been associated with phenotypically aggressive breast cancer and acquired drug-resistance. Acquired drug-resistance was modeled in cell lines from two different breast cancer subtypes, the uPAR negative luminal A subtype and the uPAR positive triple negative subtype cell line MDA-MB-231. MCF-7 cells, cultured to be resistant to tamoxifen (MCF-7 TamR), were found to significantly over-express uPAR compared to the parental cell line. uPAR expression was maintained when resistance was modeled in triple-negative breast cancer by generating doxorubicin and paclitaxel resistant MDA-MB-231 cells (MDA-MB-231 DoxR and MDA-MB-231 TaxR). Using the antagonistic uPAR antibody 2G10, uPAR was imaged in vivo by near-infrared (NIR) optical imaging and (111)In-single photon emission computed tomography (SPECT). Tumor uptake of the (111)In-SPECT probe was high in the three drug-resistant xenografts (> 46 %ID/g) and minimal in uPAR negative xenografts at 72 hours post-injection. This preclinical study demonstrates that uPAR can be targeted for imaging breast cancer models of acquired resistance leading to potential clinical applications

Reirradiation and PD-1 inhibition with nivolumab for the treatment of recurrent diffuse intrinsic pontine glioma: a single-institution experience.

BackgroundDiffuse intrinsic pontine glioma (DIPG) is a rare, aggressive brain tumor with no known cure. Reirradiation (reRT) at recurrence can prolong survival. The impact of irradiation may be heightened when combined with PD-1 inhibition. We describe our experience using reRT, with or without PD-1 inhibition, in a cohort of patients with recurrent DIPG.MethodsWe performed a retrospective cohort analysis of children who received reRT with or without concomitant PD-1 inhibition for recurrent DIPG at a single institution between 2005 and 2016. We compared progression-free (PFS) and overall survival (OS) between those who received reRT alone or in combination with PD-1 inhibition. We then compared reRT to a cohort of patients who did not receive reRT.ResultsThirty-one patients were included (8-reRT with nivolumab; 4-reRT alone; 19-no reRT). Patients who received reRT had prolonged OS compared to no reRT (22.9 months-reRT with nivolumab; 20.4 months-reRT alone; 8.3 months-no reRT; p < 0.0001). Patients who received reRT with nivolumab vs. reRT only had slightly prolonged OS from diagnosis and from reRT (22.9 vs. 20.4 months for time from diagnosis; 6.8 vs. 6.0 months for time from reRT). All patients receiving reRT with or without nivolumab tolerated the therapy without acute or late toxicity.ConclusionsOur experience demonstrates the tolerability of reRT with concurrent PD-1 inhibition for recurrent DIPG and suggests that combination therapy may offer survival benefit. Future prospective studies are needed to confirm the benefits of this combination therapy

Reirradiation and PD-1 inhibition with nivolumab for the treatment of recurrent diffuse intrinsic pontine glioma: a single-institution experience.

BackgroundDiffuse intrinsic pontine glioma (DIPG) is a rare, aggressive brain tumor with no known cure. Reirradiation (reRT) at recurrence can prolong survival. The impact of irradiation may be heightened when combined with PD-1 inhibition. We describe our experience using reRT, with or without PD-1 inhibition, in a cohort of patients with recurrent DIPG.MethodsWe performed a retrospective cohort analysis of children who received reRT with or without concomitant PD-1 inhibition for recurrent DIPG at a single institution between 2005 and 2016. We compared progression-free (PFS) and overall survival (OS) between those who received reRT alone or in combination with PD-1 inhibition. We then compared reRT to a cohort of patients who did not receive reRT.ResultsThirty-one patients were included (8-reRT with nivolumab; 4-reRT alone; 19-no reRT). Patients who received reRT had prolonged OS compared to no reRT (22.9 months-reRT with nivolumab; 20.4 months-reRT alone; 8.3 months-no reRT; p < 0.0001). Patients who received reRT with nivolumab vs. reRT only had slightly prolonged OS from diagnosis and from reRT (22.9 vs. 20.4 months for time from diagnosis; 6.8 vs. 6.0 months for time from reRT). All patients receiving reRT with or without nivolumab tolerated the therapy without acute or late toxicity.ConclusionsOur experience demonstrates the tolerability of reRT with concurrent PD-1 inhibition for recurrent DIPG and suggests that combination therapy may offer survival benefit. Future prospective studies are needed to confirm the benefits of this combination therapy

Brain metastasis growth on preradiosurgical magnetic resonance imaging

Purpose: A previous analysis showed that brain metastases that are treated with frameless stereotactic radiation surgery (SRS) and planned with magnetic resonance imaging (MRI) \u3e14 days before SRS had worse local control (LC). To evaluate if worse LC may be due to unaccounted interval metastasis growth and radiosurgical marginal miss, we quantified growth before SRS on preradiosurgical imaging. Methods and materials: We reviewed data from patients who were treated with fixed-frame SRS for brain metastases at our institution between 2010 and 2013 and had pretreatment diagnostic brain MRI and SRS-planning MRI scans available. Metastases were contoured on the pretreatment MRI scan and the day-of-treatment planning MRI scan for volumetric comparison. Growth rates were calculated. Serial volumetric contour expansions on the pretreatment MRI scans were used to determine the minimum margin necessary to encompass the entire metastasis on day of the SRS. LC was estimated by Kaplan-Meier method. Results: Among 411 brain metastases in 165 patients, the time between pretreatment and treatment MRI was associated with metastasis growth (P \u3c.001) with a mean growth rate of 0.02 ml/day (95% confidence interval, 0.01-0.03) and a 1.35-fold volume increase at 14 days. Time between MRI scans was associated with the amount of margin that was needed to target the entire brain metastasis volume on the day of the SRS (P \u3c.001), as were volume of metastasis on the pre-treatment MRI (P \u3c.001) and melanoma histology (P \u3c.001). LC was not associated with growth rate among patients who underwent fixed-frame SRS. Conclusions: Time between pretreatment MRI and SRS is associated with brain metastasis growth, but LC is not compromised when patients receive fixed-frame SRS with same-day MRI planning. Margins may be needed for metastases that are treated with frameless SRS to account for growth between the planning MRI and SRS delivery. In this study, we quantify brain metastasis growth over time by taking advantage of the availability of 2 pretreatment magnetic resonance imaging scans taken at 2 time points among patients treated with frame-fixed radiation surgery. We found that metastasis growth is associated with time, initial metastasis size, melanoma histology, and concurrent chemotherapy. Performing serial margin expansions demonstrated factors that are associated with the amount of margin that is needed to target the entire metastasis on the day of radiation surgery