Research
Research in the Frank Lab focuses on investigating the biological differences in signaling pathways after helium versus proton versus photon radiotherapy, which will facilitate the selection of different radiation modalities (helium, proton, photon, ultra-high dose rate [FLASH] or conventional dose rate radiation), as well as the combination of radiation with other treatments, including targeted therapy and immunotherapy. We are also developing radiation toxicity-mitigating agents to decrease radiation-induced toxicity for patients with head and neck or prostate cancers. Finally, our research also includes the development and optimization of novel positive contrast multi-imaging modality fiducial markers that promote MRI-assisted radiosurgery (MARS) for patients with prostate cancer in community-based treatment centers. Overall, we aim to improve treatments for patients with head and neck or prostate cancers.
Further expansion of our research
Although photons can kill tumors, they also cause significant acute and chronic damage to normal tissues. Therapy with charged particles like protons or carbon ions may lead to better treatment outcomes but bear uncertainties in improving treatment effects. Our institution is initiating a novel alternative — helium ion therapy — delivered to seated patients to treat various types of cancer. In our lab, we are proposing a series of tests of this new therapy that will culminate in a new understanding of the physics and pre-clinical biology of the therapy, as well as a Phase II randomized clinical trial with cancer patients.
Our research in head & neck cancer
Improving proton radiation therapy
Modern-day photon (x-ray)-based radiation therapy (XRT) given with chemotherapy, has improved survival outcomes for patients with head and neck squamous cell carcinoma (HNSCC). However, the acute and long-term side effects of this therapy have prompted the search for more biologically sound therapeutic strategies. Proton radiation therapy may be less toxic to nearby normal tissues than photon radiation and as such would be ideal for HNSCC. However, proton facilities are scarce, and proton therapy is expensive to deliver, so the ability to identify patients with tumors that will respond better to proton than photon radiation would help to ensure the best use of limited resources. To date, no such markers of response have been identified. Other unknowns associated with proton therapy involve identifying personalized relative biological effectiveness (RBE) values and the linear energy transfer (LET) effect on RBE for protons versus photons (rather than using the constant of 1.1). Our long-term objectives are:
- To reduce proton radiation therapy dose uncertainties
- To identify biomarkers enabling us to identify which patients are more (or less) likely to benefit from proton (versus photon) radiation therapy
- To identify new molecular targets that, when used in combination with proton radiation therapy, will maximize treatment benefits in HNSCC
From our benchside research thus far, we have found that:
- The RBE value of proton (versus photon) in HNSCC is cell line-dependent and is influenced by radiation fraction size.
- Compared to photon radiation therapy, proton radiation therapy caused more persistent DNA double-strand breaks, induced more senescence and mitotic catastrophe as cell death mechanisms and led to different protein expression and activation profiles. This indicates photons tended to induce lower expression of DNA damage repair (DDR)- and cell cycle arrest-related proteins and higher expression of cell survival- and proliferation-related proteins.
- Targeting DDR with PARP1/2 or CHK1 inhibition can enhance the response of HNSCC cells to proton versus photon radiation therapy.
- Putting tumors at the distal edge (versus at the middle) of the spread-out Bragg peak (SOBP) led to longer overall survival time in mice with certain types of HNSCC tumors.
Ultra-high dose rate (FLASH) radiation
Recently, there were extensive efforts to develop new radiation delivery approaches to further protect normal tissues while enabling curative radiation doses to oropharyngeal carcinomas. A novel promising modality is ultra-high dose rate (FLASH) radiation therapy, which delivers the entire curative dose to a tumor in one treatment that lasts only milliseconds, while mitigating normal tissue damage. This feature can eliminate organ and tumor motion during each fraction to empower radiation dose accuracy and reproducibility of treatment settings. However, research on FLASH radiation is still in its infancy with many unknowns, and studies on normal tissues and tumors in the head and neck region are absent. Our ongoing investigations are focused on:
- Elucidating the effects and mechanisms of FLASH (electron, photon and proton) radiotherapy on normal tissues and tumors in the head and neck region
- Identifying the most optimized radiation fraction size and fraction numbers to provide evidence for the future clinical application of FLASH to patients with HNSCC
Mitigating radiation toxicities
Significant radiation-related short- and long-term toxicities can worsen patient quality of life and cause economic problems, subsequently influencing tumor control and even contributing to mortality. Rusalatide acetate (TP508) is a synthetic 23-amino-acid peptide that resembles a fragment of human thrombin. Human thrombin has been recognized as a radiation toxicity mitigator through an initial response that results in an anti-inflammatory response which promotes recovery, repair and angiogenesis without stimulating any of the events associated with blood clotting by thrombin. From our bench side research, we have found that:
- TP508 appears to especially protect human lens epithelial (HLE) cells from radiation killing.
- TP508 seems to mitigate the radiation killing of HLE cells through regulation of the DNA damage repair response, especially the radiation killings caused by proton radiation.
In light of these findings, our current research in this area is focused on studying the effect of TP508 in mitigating radiation-induced immune system changes in eyes, using perfluorocarbon nanoparticles and 19F MRI to characterize the changes.
Comparing proton and photon radiotherapy
Toxicity and tumor control outcomes
Dr. Frank is the Principal Investigator of a National Institutes of Health (NIH)/National Cancer Institute (NCI)-sponsored Phase III randomized trial (NCT01893307) in oropharyngeal cancer that compares toxicity and tumor control outcomes after chemoradiation using intensity-modulated radiation therapy (IMRT) versus intensity-modulated proton therapy (IMPT). Blood and tumor samples collected from patients enrolled in this clinical trial will be used to identify biomarkers that facilitate clinical decision making to enable personalized precision radiation and systematic treatment that can improve treatment outcomes while mitigating treatment-related toxicities in patient with HNSCC.
While continuing the follow-up of patients, we are currently focused on a multiple-PI collaborative study (P01) which aims to improve lifelong quality of life (QOL) and health among oropharyngeal cancer (OPC) survivors by delivering non-invasive clinic-ready markers of delayed adverse treatment sequelae and other novel mitigation strategies. In this study, we aim to:
- Generate toxicity risk-predicting models
- Identify biomarkers and imaging markers related to toxicity development
- Identify patients at high risk of developing treatment-related toxicities
- Develop intervention agents to prevent and treat toxicities
Effect on taste function
Modern chemoradiation treatment for head and neck cancers has a high risk of causing severe XRT-induced impairment in taste function which, in turn, is associated with weight loss and subsequent poor survival outcomes. Proton radiation therapy (PRT) may be less toxic to nearby normal tissues compared to XRT and is expected to cause less impairment in taste function because smaller amounts of taste buds, oral mucosa and salivary glands are exposed to radiation relative to XRT. With data derived from our Phase III randomized trial, we aim to:
- Determine the effects of proton versus x-ray radiation on individual components of taste
- Identify the risk factors of proton- and photon-induced changes in taste function
- Generate an incidence risk-predicting model of developing proton- and x-ray-induced taste function impairments
Effect on the microbiome
Finally, we are utilizing the trial data to investigate changes in lymphopenia and microbiome populations in patients treated with proton and photon radiotherapy to provide useful indications for immunotherapy.
Proton therapy for localized adenoid cystic carcinoma
Surgery followed by XRT is standard therapy for patients with localized adenoid cystic carcinoma (ACC) presenting in the head and neck region (orbital and periocular region). However, ACCs are aggressive tumors that are often advanced, with local invasion and perineural invasion at the time of diagnosis. Definitive XRT can, theoretically, cure unresectable or recurrent ACC; however, the numerous critical structures in the head and neck region generally preclude the use of definitive XRT doses, and the local tumor control rates are correspondingly low. Proton radiation therapy may be less toxic than XRT to nearby normal tissues and thus would be ideal for ACC. Our research in this area is focused on:
- Establishing how ACC responds at a molecular level to proton radiation therapy versus XRT to identify novel clinically relevant targets for combination treatment
- Testing whether blocking DNA damage repair or cell proliferation pathways can enhance the effectiveness of proton or XRT in ACC
- Testing the effect of TP508 in mitigating normal tissue damages in in vivo ACC models (eyes)
Our research in prostate cancer
Comparing proton and photon radiotherapy
Prostate cancer is the most common cancer and the second leading cause of cancer death among men in the United States. Although modern external beam photon radiotherapy (IMRT) is a mainstay of therapy for patients with prostate cancer, photon radiation-related acute and chronic urinary and bowel toxicity worsens quality of life.
Proton radiotherapy is effective in treating prostate cancer, with favorable disease control and toxicity outcomes. However, radiobiologic evidence of the advantages of proton versus photon radiotherapy for prostate is limited, and the molecular responses of prostate cells to protons versus photons are unclear. We are studying the molecular effects of proton versus photon radiation therapy in human prostate cell lines.
Proton external beam radiation therapy may be less toxic than photon because it minimizes the exposure of normal tissues. A recent study including several nationwide proton facilities indicated that compared with photon therapy, proton therapy led to lower rates of multidomain urinary toxicity (39.1% vs 48.3% at 3 years). We have found that definitive local therapy for T4 prostate cancer is associated with improved local control and survival.
With the large number of patients treated with photon or proton radiation in our institution, our research in prostate cancer is focused on the comparison of toxicity and tumor control outcomes after intensity-modulated radiation therapy (IMRT) versus intensity-modulated proton therapy (IMPT). We are also exploring the development of risk-predicting models to identify the better choice between proton or photon radiation for specific patients. Moreover, considering tumor and normal organ motion within and between radiation fractions that negatively influences treatment outcomes in prostate cancers, we are also exploring the feasibility of applying specially fractionated mini-beam proton radiation therapy for prostate cancers.
FLASH radiation for prostate cancer
Ultra-high dose rate (FLASH) radiation therapy is a promising strategy to mitigate radiation related toxicities. However, FLASH radiation's effects on tumors and normal tissues in prostate cancers are still unknown. We are investigating these effects in our ongoing studies, which aim to:
- Elucidate the effects and mechanisms of FLASH (electron, photon and proton) radiotherapy on normal tissues and tumors in prostate cancers and pelvic normal tissues
- Identify the most optimized radiation fraction size and fraction numbers to provide evidence for the future clinical application of FLASH for patients with prostate cancers
MRI-assisted radiosurgery (MARS)
Brachytherapy, or internal radiation treatment, is considered one of the most attractive treatments for prostate cancer because of its well-established improved quality of life outcomes and comparable or improved disease-specific survival and overall survival rates when compared to surgery and external beam radiation therapy. Nevertheless, treatment toxicity can compromise patient quality of life if bowel, bladder, urethra and sexual organ dose tolerances are exceeded.
Current imaging techniques (i.e., ultrasound and computed tomography [CT]) are inadequate to assess the quality of the radiation treatment delivery. Because the soft tissue resolution of magnetic resonance imaging (MRI) makes it possible to distinguish prostate tumors from surrounding normal tissues, MRI is the optimal imaging modality to accomplish the goal of precise target delineation and subsequent dose maximization of brachytherapy for prostate tumors, as well as to minimize risk to adjacent organs at risk (OARs). However, the radioactive seeds appear as negative signal voids, and post-implant dosimetry cannot be performed using MRI.
Recognizing the problems inherent in the quality of prostate brachytherapy, we have developed a novel MRI-positive contrast agent (cobalt-chloride), with funding support from the NIH, Prostate Cancer Foundation, Texas Ignition Fund and MD Anderson. This agent now has several US and international patents issued, and its production was licensed from MD Anderson for commercialization by C4 Imaging, a start-up company founded by Dr. Frank. Cobalt-chloride is now Food and Drug Administration (FDA) 510k-cleared for use in the treatment of prostate cancer with brachytherapy.
Using this novel C4 MRI marker, we developed the novel prostate cancer treatment approach of MRI-Assisted Radiosurgery (MARS) with brachytherapy for patients with prostate cancer. MARS with brachytherapy is now being used for patients with prostate cancer, with the goal of improving cure rates and decreasing treatment-related toxicities. Furthermore, the Frank Lab completed accrual and published a Phase II clinical trial of 300 prostate cancer patients with monotherapy for intermediate-risk localized disease.
Expanding MARS access to community-based centers
Most community-based treatment centers do not have dedicated imaging physics support. To make possible the expansion of the application of MARS from a few top academic centers to community-based treatment centers, we are developing an optimized MRI package with the proper sequences and parameters for MARS for marker visualization.
The outcome of this research is expected to improve the quality, accuracy and outcomes of MARS treatment by reducing the uncertainties of the existing US-CT-based approaches and greatly expanding the use of MARS for prostate cancer treatment in community-based treatment centers.
Novel markers for accurate comparison of MR and CT images
Because radiation treatment planning systems are currently still CT-based, in order to utilize MRI, CT-MRI fusion is required. However, in clinical practice, the fusion software is often inadequate due to different bladder and rectal filling at the times of image acquisition and cognitive fusion (i.e., side-to-side comparison of MRI and CT images).
To address these limitations, we are developing and optimizing novel positive contrast multi-imaging modality fiducial markers (positively visualized on MRI, CT and KV X-ray) to facilitate the accuracy of CT and MRI image registration.