University of Pennsylvania
Radiation Oncology
Professor in the Department of Radiation Oncology at the University of Pennsylvania and Associate Director of the Division of Oncology Research in this department. Led more than two decades of translational research on the microenvironments of tumor and normal tissues as they respond to radiation therapies, including nonionizing radiation in the form of photodynamic therapy and ionizing radiation with photons or protons. Central to this research is a long-standing interest in the study of dose rate as a determinant of therapeutic outcome to radiation therapy. At the ultra-high dose rates of FLASH proton radiotherapy, we are actively investigating mechanisms of normal tissue sparing and antitumor efficacy.

Moderator of 1 Session

Session Type
Plenary Session
Date
Thu, 02.12.2021
Session Time
18:20 - 19:20
Room
Hall C
Session Description
The session will include voting.

Presenter of 3 Presentations

The Differential Effects of FLASH Dose Rate in Proton Radiotherapy of Epithelial Tissues: from Necrosis to Fibrosis

Session Type
Industry Sponsored Session
Date
Thu, 02.12.2021
Session Time
12:10 - 13:10
Room
Hall C
Lecture Time
12:15 - 12:30

MECHANISMS OF FLASH RADIOTHERAPY SPARING OF NORMAL TISSUE AS INFORMED BY RNA-SEQ TRANSCRIPTOME ANALYSES

Session Type
FLASH Mechanisms Track
Date
Fri, 03.12.2021
Session Time
12:30 - 13:00
Room
Hall C
Lecture Time
12:30 - 12:35

Abstract

Background and Aims

The ultra-high dose rates of FLASH radiotherapy can reduce the severity of both acute damage and chronic side effects from radiation of normal tissues. For many disease sites, treatment with radiotherapy puts the skin at risk of toxicities that compromise its barrier and protective functions. Using RNAseq, we investigated the effects of FLASH versus standard proton radiotherapy on skin, identifying transcriptome-level differentials in response that inform mechanisms by which FLASH may spare normal tissues from radiotherapy-induced toxicities.

Methods

Clinical and histological responses of C57BL/6 mice to FLASH and standard proton radiotherapy were assessed for respective dose rates of 69-124 Gy/sec and 0.39-0.65 Gy/sec. RNAseq was performed of full thickness skin, collected at 5 days after irradiation. All studies irradiated the mouse hind limb to a total dose of 30 Gy.

Results

FLASH proton radiotherapy (F-PRT) significantly spared murine skin relative to standard proton radiotherapy (S-PRT), with corroborating pathological findings that F-PRT produced less epidermal necrosis than S-PRT. From RNAseq data, pathways upregulated by S-PRT included those involved in apoptosis and keratin signaling. In contrast, F-PRT increased signaling in pathways related to tissue and vascular repair, such as blood vessel morphogenesis and vascular development. Genes that were differentially uprelated after F-PRT included platelet/endothelial cell adhesion molecule and family members of the matrix metalloproteinases and fibroblast growth factors that associate with wound healing.

Conclusions

RNAseq analyses offer insight in mechanisms of F-PRT sparing that include greater induction of tissue damage by S-PDT and more upregulation of repair by F-PRT.

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Author Of 6 Presentations

The Differential Effects of FLASH Dose Rate in Proton Radiotherapy of Epithelial Tissues: from Necrosis to Fibrosis

Session Type
Industry Sponsored Session
Date
Thu, 02.12.2021
Session Time
12:10 - 13:10
Room
Hall C
Lecture Time
12:15 - 12:30

MECHANISMS OF FLASH RADIOTHERAPY SPARING OF NORMAL TISSUE AS INFORMED BY RNA-SEQ TRANSCRIPTOME ANALYSES

Session Type
FLASH Mechanisms Track
Date
Fri, 03.12.2021
Session Time
12:30 - 13:00
Room
Hall C
Lecture Time
12:30 - 12:35

Abstract

Background and Aims

The ultra-high dose rates of FLASH radiotherapy can reduce the severity of both acute damage and chronic side effects from radiation of normal tissues. For many disease sites, treatment with radiotherapy puts the skin at risk of toxicities that compromise its barrier and protective functions. Using RNAseq, we investigated the effects of FLASH versus standard proton radiotherapy on skin, identifying transcriptome-level differentials in response that inform mechanisms by which FLASH may spare normal tissues from radiotherapy-induced toxicities.

Methods

Clinical and histological responses of C57BL/6 mice to FLASH and standard proton radiotherapy were assessed for respective dose rates of 69-124 Gy/sec and 0.39-0.65 Gy/sec. RNAseq was performed of full thickness skin, collected at 5 days after irradiation. All studies irradiated the mouse hind limb to a total dose of 30 Gy.

Results

FLASH proton radiotherapy (F-PRT) significantly spared murine skin relative to standard proton radiotherapy (S-PRT), with corroborating pathological findings that F-PRT produced less epidermal necrosis than S-PRT. From RNAseq data, pathways upregulated by S-PRT included those involved in apoptosis and keratin signaling. In contrast, F-PRT increased signaling in pathways related to tissue and vascular repair, such as blood vessel morphogenesis and vascular development. Genes that were differentially uprelated after F-PRT included platelet/endothelial cell adhesion molecule and family members of the matrix metalloproteinases and fibroblast growth factors that associate with wound healing.

Conclusions

RNAseq analyses offer insight in mechanisms of F-PRT sparing that include greater induction of tissue damage by S-PDT and more upregulation of repair by F-PRT.

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FLASH PROTON RADIOTHERAPY IS EQUIPOTENT TO STANDARD RADIATION IN TREATMENT OF MURINE SARCOMAS WHILE REDUCING TOXICITIES TO NORMAL SKIN, MUSCLE AND BONE

Session Type
FLASH Mechanisms Track (Oral Presentations)
Date
Wed, 01.12.2021
Session Time
10:20 - 11:30
Room
Room 2.15
Lecture Time
10:20 - 10:30

Abstract

Background and Aims

Compared to Standard dose rates, the high dose rates of FLASH radiation can reduce radiotherapy toxicities to normal tissues. We examined the potential of FLASH-proton radiotherapy (F-PRT) to treat murine sarcomas and protect normal epithelial and mesenchymal tissues relative to the effects of standard-proton radiotherapy (S-PRT).

Methods

Mice received 30 or 45 Gy of F-PRT (69-124 Gy/sec) or S-PRT (0.39–0.65 Gy/sec) to their hind legs. Skin, muscle and bone injuries were recorded as acute through chronic macroscopic and/or microscopic observations of radiation-induced damage. Murine skin and bone RNAseq analyses were performed to delineate involved mechanisms. Skin stem cell depletion, inflammatory reaction and TGF-β levels were evaluated, and antitumor efficacy of F-PRT was compared to S-PRT in two murine models of sarcoma.

Results

Fewer severe morbidities were induced by F-PRT, with RNAseq revealing S-PRT to upregulate pathways involved in apoptosis signaling and keratinocyte differentiation in skin, and osteoclast differentiation and chondrocyte development in bone. Accordingly, F-PRT reduced skin injury, stem cell depletion and inflammation; mitigated lymphedema; and decreased myofiber atrophy, bone resorption, hair follicle atrophy, and epidermal hyperplasia. Equipotent control of sarcoma growth was achieved by the radiation modalities. Finally, S-PRT produced higher levels of TGF-β1 in murine skin than did F-PRT, and this finding was corroborated in the skin samples of dogs treated on a F-PRT clinical trial.

Conclusions

F-PRT can alleviate radiation-induced damage to both epithelial and mesenchymal tissues without compromise to sarcoma response; continuing investigation will further F-PRT translation to the clinic.

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A RANDOMIZED DOSE ESCALATION STUDY OF FLASH VS STANDARD DOSE RATE PROTON RADIOTHERAPY FOR CANINE OSTEOSARCOMA

Session Type
FLASH in the Clinic Track (Oral Presentations)
Date
Wed, 01.12.2021
Session Time
14:50 - 15:50
Room
Room 2.31
Lecture Time
14:50 - 15:00

Abstract

Background and Aims

To examine the impact of ultra-high dose rate, “FLASH,” proton RT (F-PRT) vs standard dose rate PRT (S-PRT), we have performed a randomized dose escalation study of F-PRT vs S-PRT for dogs with osteosarcoma (OSA). Standard of care treatment typically involves complete or partial amputation, allowing for pathological and molecular examination of tumor vs normal tissue PRT effects.

Methods

Following owner signing informed consent, dogs were randomly assigned to F-PRT vs S-PRT at escalating doses from 4-24 Gy. Under fluoroscopic guidance, fields were designed to treat segments of tumor vs normal metaphyseal bone. Five days after PRT, dogs underwent limb amputation and samples of tumor, normal bone, skin and subcutaneous soft tissues were collected from irradiated and unirradiated sites.

Results

To date 27 dogs have completed treatment, with 4 remaining dogs to be treated in the 24 Gy cohort. Acute toxicity following PRT has been observed in 2 dogs, with one dog having a pathologic fracture and one dog experiencing intertumoral hemorrhage following treatment with 12 Gy S-PRT and F-PRT, respectively. Preliminary histologic analyses suggest no difference in tumor necrosis between F-PRT and S-PRT and molecular analysis demonstrates F-PRT dramatically reduces induction of TGF-beta signaling in normal tissues as compared to S-PRT. More detailed molecular studies using RNAseq are ongoing to help define mechanisms of F-PRT effects.

Conclusions

We have performed the first study of F-PRT in dogs with spontaneous OSA demonstrating both the clinical feasibility and potential utility of this novel modality in a genetically heterogeneous model system.

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ULTRAFAST TRACKING OF OXYGEN DYNAMICS DURING PROTON FLASH

Session Type
FLASH Mechanisms Track (Oral Presentations)
Date
Wed, 01.12.2021
Session Time
18:00 - 19:00
Room
Room 2.15
Lecture Time
18:30 - 18:40

Abstract

Background and Aims

Radiotherapy at ultrahigh dose rates (FLASH, >40Gy/sec) compared to conventional radiotherapy (CR; <1 Gy/sec) has been shown to provide an advantage by selective protection of normal versus tumor tissue. Depletion of molecular oxygen causing radioprotection has been proposed to underpin the FLASH effect, however no experimental data have been presented to test this hypothesis. Our goal was to assess the oxygen dynamics during and following proton FLASH versus CR.

Methods

Measurements of oxygen were performed in vitro (solutions in sealed vials) and in vivo in mice (healthy leg muscle and tumors) using the phosphorescence quenching method with probe Oxyphor PtG4 at rates reaching 3 measurements/millisecond during proton irradiation delivered with CR or FLASH dose rates.

Results

In closed systems in vitro the rate of oxygen depletion is oxygen-independent for both FLASH and CR when [O2]>~70 μM. The g-values are lower for FLASH than for CR by ~15%. In vivo oxygen is depleted upon FLASH with rates that correlate with baseline pO2 (partial pressure of oxygen) values throughout the entire pO2 range: at 30-40 mmHg (normal tissue) a 30 Gy FLASH (100 Gy/s) results in ΔpO2 of -8 mmHg, while at 5-7 mmHg (tumor) ΔpO2 is only -1 mmHg.

Conclusions

This study features the first demonstration of the phosphorescence quenching oximetry at ultrafast rates and in the presence of proton radiation. Oxygen depletion by FLASH in vitro was found to be smaller than by CR, and appears to correlate with baseline pO2 values, being greater for normal tissue than for tumors.

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