Inhibitors of poly(ADP-ribose) polymerase (PARP) are in clinical trials for cancer therapy, on the basis of the role of PARP in recruitment of base excision repair (BER) factors to sites of DNA ...damage. Here we show that PARP inhibition to block BER is toxic to hypoxic cancer cells, in which homology-dependent repair (HDR) is known to be down-regulated. However, we also report the unexpected finding that disruption of PARP, itself, either via chemical PARP inhibitors or siRNAs targeted to PARP-1, can inhibit HDR by suppressing expression of BRCA1 and RAD51, key factors in HDR of DNA breaks. Mechanistically, PARP inhibition was found to cause increased occupancy of the BRCA1 and RAD51 promoters by repressive E2F4/p130 complexes, a pathway prevented by expression of HPV E7, which disrupts p130 activity, or by siRNAs to knock down p130 expression. Functionally, disruption of p130 by E7 expression or by siRNA knockdown also reverses the cytotoxicity and radiosensitivity associated with PARP inhibition, suggesting that the down-regulation of BRCA1 and RAD51 is central to these effects. Direct measurement of HDR using a GFP-based assay demonstrates reduced HDR in cells treated with PARP inhibitors. This work identifies a mechanism by which PARP regulates DNA repair and suggests new strategies for combination cancer therapies.
TH-302 is a 2-nitroimidazole triggered hypoxia-activated prodrug (HAP) of bromo-isophosphoramide mustard currently undergoing clinical evaluation. Here, we describe broad-spectrum activity, ...hypoxia-selective activation, and mechanism of action of TH-302. The concentration and time dependence of TH-302 activation was examined as a function of oxygen concentration, with reference to the prototypic HAP tirapazamine, and showed superior oxygen inhibition of cytotoxicity and much improved dose potency relative to tirapazamine. Enhanced TH-302 cytotoxicity under hypoxia was observed across 32 human cancer cell lines. One-electron reductive enzyme dependence was confirmed using cells overexpressing human NADPH:cytochrome P450 oxidoreductase and radiolytic reduction established the single-electron stoichiometry of TH-302 fragmentation (activation). Examining downstream effects of TH-302 activity, we observed hypoxia-dependent induction of γH2AX phosphorylation, DNA cross-linking, and cell-cycle arrest. We used Chinese hamster ovary cell-based DNA repair mutant cell lines and established that lines deficient in homology-dependent repair, but not lines deficient in base excision, nucleotide excision, or nonhomologous end-joining repair, exhibited marked sensitivity to TH-302 under hypoxia. Consistent with this finding, enhanced sensitivity to TH-302 was also observed in lines deficient in BRCA1, BRCA2, and FANCA. Finally, we characterized TH-302 activity in the three-dimensional tumor spheroid and multicellular layer models. TH-302 showed much enhanced potency in H460 spheroids compared with H460 monolayer cells under normoxia. Multicellular layers composed of mixtures of parental HCT116 cells and HCT116 cells engineered to express an oxygen-insensitive bacterial nitroreductase showed that TH-302 exhibits a significant bystander effect.
Radiation therapy represents a pillar in the current management of breast cancer. Historically, postmastectomy radiation therapy (PMRT) has been administered only in patients with locally advanced ...disease and a poor prognosis. These included patients with large primary tumors at diagnosis and/or more than three metastatic axillary lymph nodes. However, during the past few decades, several factors have prompted a shift in perspective, and recommendations for PMRT have become more fluid. Guidelines for PMRT in the United States are outlined by the National Comprehensive Cancer Network and the American Society for Radiation Oncology. Because evidence to support performing PMRT is frequently discordant, the decision to offer radiation therapy often requires team discussion. These discussions are usually held in multidisciplinary tumor board meetings in which radiologists play a pivotal role by providing critical information such as the location and extent of disease. Breast reconstruction after mastectomy is optional and is safe in cases in which the patient's clinical status allows it. The preferred method in the setting of PMRT is autologous reconstruction. If this is not possible, then a two-step implant-based reconstruction is recommended. Radiation therapy does involve a risk of toxicity. Complications can be seen in acute and chronic settings and range from fluid collections and fractures to radiation-induced sarcomas. Radiologists have a key role in detecting these and other clinically relevant findings and should be prepared to recognize, interpret, and address them.
RSNA, 2023 Quiz questions for this article are available in the supplemental material.
Radiation therapy (RT) provides an effective and often rapid means to alleviate symptomatic progression in pediatric patients with advanced or metastatic cancer. As part of a comprehensive, ...multimodality approach to pediatric palliative care, RT can be a useful tool to manage pain, spinal cord compression, dyspnea, neurologic compromise, bleeding, and bowel or urinary obstruction. Whether such symptoms present earlier in the disease course or in children and adolescents approaching the end of life, they can significantly impact the quality of life of patients and caregivers. Control of symptoms is therefore an important aspect in maximizing end of life care. Outcomes for palliative RT in both children and adults are favorable. While RT has been widely adopted as a component of palliative oncologic care for many adult malignancies, it remains infrequently utilized in pediatric patients despite the relative radiosensitivity of many pediatric tumors. Potential barriers to palliative radiation for pediatric patients include insufficient understanding by care providers regarding the utility of RT for a given symptom, lack of comfort in discussing a transition away from definitive management, concern over radiation-related side effects, and hesitancy toward radiation treatment on the part of parents and caregivers. Delivery of palliative RT can also be impeded by logistical obstacles including lack of on-site radiation facilities, unavailability of radiation oncologists comfortable with pediatric treatments, and the potential need for specialized medical care such as pediatric anesthesia. The aim of this review is to foster a more complete understanding of the benefits and limitations of palliative RT in the pediatric oncology setting, including common symptoms experienced by children and adolescents with cancer that may be indications for the integration of RT into palliative care paradigms, as well as the expected efficacy of treatment. We describe the logistics, delivery, common doses for palliative radiation regimens, and management of potential side effects. While palliative RT is generally well tolerated in the pediatric population, we also discuss potential side effects of RT to various body sites and approaches for prevention or mitigation.
We report a case of a 72-year-old male who presented to the hospital with a chief complaint of diplopia in the setting of a recent onset of urinary incontinence and right-sided back pain. He was ...subsequently diagnosed with prostate cancer, notably metastasizing to the right sphenoid bone, causing impingement of the oculomotor nerve. Our case is unique in that the patient's initial presentation of prostate cancer was oculomotor nerve palsy with subsequent histologic analysis of the primary tumor showing both small cell neuroendocrine carcinoma along with adenocarcinoma. Also, the initial routine stroke protocol MRI and computed tomography angiography (CTA) missed the lesion, while gadolinium-enhanced targeted MRI revealed lesions in both the spine and the orbit. This case emphasizes the need for enhanced contrast as well as focused imaging in patients presenting with diplopia with a negative initial workup for stroke. Ptosis can be a sign of metastasis from other cancers and it is important to have a broad differential including metastatic disease in patients' presenting with similar symptoms and negative initial workup who may otherwise be at risk of cancer.
Background. The majority of patients with localized Ewing sarcoma will remain disease-free long term, but for those who suffer recurrence, successful treatment remains a challenge. Identification of ...clinicopathologic factors predictive of recurrence could suggest areas for treatment optimization. We sought to describe our experience regarding predictors of recurrence and patterns of first failure in patients receiving modern systemic therapy for nonmetastatic Ewing sarcoma. Methods. The medical records of pediatric and adult patients treated for localized Ewing sarcoma between 1999 and 2019 at Johns Hopkins Hospital were retrospectively analyzed. Local control was surgery, radiotherapy, or both. Recurrence-free survival (RFS) was calculated using the Kaplan–Meier method. Univariable and multivariable Cox proportional-hazards modeling was performed to obtain hazard ratios (HR) for recurrence. Results. In 94 patients with initially localized disease, there were 21 recurrences: 4 local, 14 distant, and 3 combined. 5-year and 10-year RFS were 75.6% and 70.5%, respectively. On multivariable analysis including age at diagnosis and tumor size, <95% tumor necrosis following neoadjuvant chemotherapy (NAC; HR 14.3, p = 0.028) and radiological tumor size change during NAC (HR 1.04 per 1% decrease in size change, p = 0.032) were independent predictors of recurrence. Among patients experiencing distant recurrence, pulmonary metastases were present in 82% and were the only identifiable site of disease in 53%. Conclusions. Poor pathologic or radiologic response to NAC is predictive of recurrence in patients with localized Ewing sarcoma. Suboptimal tumor size reduction following chemotherapy provides a means to risk-stratify patients who do not undergo definitive resection. Isolated pulmonary recurrence was a common event.
To inform development of procedures for using tumor-treating field arrays (TTFields) during glioblastoma radiation therapy by determining whether the placement and repositioning of arrays affects ...target volume coverage and cranial skin dose.
Radiation plans from 10 consecutive patients treated for glioblastoma were copied to a cranial phantom and reoptimized for phantom anatomy. Dose distributions were then recalculated on 3 additional computed tomographic scans of the phantom with the TTFields electrode arrays placed over distinct locations on the phantom scalp to compare planning target volume (PTV) coverage and skin dose with and without TTFields in place in varying positions. Percent depth dose curves were also measured for radiation beams passing through the electrodes and compared with commonly used bolus material.
The presence of TTFields arrays decreased PTV V97% and D97% by as much as 1.7% and 2.7%, respectively, for a single array position, but this decrease was mitigated by array repositioning. On averaging the 3 array positions, there was no statistically significant difference in any dosimetric parameter of PTV coverage (V95-97%, D95-97%) across all cases compared with no array. Mean increases in skin D1cc and D20cc of 3.1% were calculated for the cohort. Surface dose for TTFields electrodes was less than that with a 5-mm superflab bolus.
Our work demonstrates that placement of TTFields arrays does not significantly affect target volume coverage. We show that repositioning of TTFields arrays, as is required in clinical use, further minimizes any dosimetric changes and eliminates the need for replanning when arrays are moved. A slight, expected bolus effect is observed, but the calculated increases in skin dose are not clinically significant. These data support the development of clinical trials to assess the safety and efficacy of combining concurrent chemoradiotherapy with TTFields therapy for glioblastoma.
Radiotherapy and DNA-damaging chemotherapy are frequently utilized in the treatment of solid tumors. Innate or acquired resistance to these therapies remains a major clinical challenge in oncology. ...The development of small molecules that sensitize cancers to established therapies represents an attractive approach to extending survival and quality of life in patients. Here, we demonstrate that YU238259, a member of a novel class of DNA double-strand break repair inhibitors, exhibits potent synthetic lethality in the setting of DNA damage response and DNA repair defects. YU238259 specifically inhibits homology-dependent DNA repair, but not non-homologous end-joining, in cell-based GFP reporter assays. Treatment with YU238259 is not only synergistic with ionizing radiation, etoposide, and PARP inhibition, but this synergism is heightened by BRCA2 deficiency. Further, growth of BRCA2-deficient human tumor xenografts in nude mice is significantly delayed by YU238259 treatment even in the absence of concomitant DNA-damaging therapy. The cytotoxicity of these small molecules in repair-deficient cells results from an accumulation of unresolved DNA double-strand breaks. These findings suggest that YU238259 or related small molecules may have clinical benefit to patients with advanced BRCA2-negative tumors, either as a monotherapy or as an adjuvant to radiotherapy and certain chemotherapies.
We have identified a novel series of compounds that demonstrate synthetic lethality in DNA repair-deficient cell and animal models and have strong potential for clinical translation.
Base excision repair (BER) plays a critical role in the repair of bases damaged by oxidative metabolism or alkylating agents, such as those commonly used in cancer therapy. Incomplete BER generates ...intermediates that require activation of homology-dependent DNA repair to resolve. We investigated the effects of lithocholic acid (LCA), an inhibitor of the key BER enzyme DNA polymerase beta (pol beta), in cells deficient in expression of the homology-dependent repair factor BRCA2. In vitro studies show that LCA suppresses the DNA polymerase and 5'-deoxyribose phosphate lyase activities of DNA pol beta by preventing the formation of a stable pol beta-DNA complex, reducing BER effectiveness. Cytotoxicity assays based on colony formation revealed that LCA exhibits synergism with the alkylating agent temozolomide, which engages BER through DNA methylation, and that the degree of synergism is increased in cells lacking functional BRCA2. BRCA2-deficient cells also showed heightened susceptibility to both LCA and temozolomide individually. The potentiation of temozolomide cytotoxicity by LCA owes to the conversion of single-stranded DNA breaks generated through incomplete BER of methylated nucleotides into double-stranded breaks during DNA replication, as indicated by gammaH2AX immunofluorescence. Death seems to be induced in cotreated cells through an accumulation of persistent double-stranded DNA breaks. Mutations of the BRCA2 gene have been extensively characterized and are present in various cancers, implying that inhibition of BER may offer a means to augment tumor selectivity in the use of conventional cancer therapies.
This retrospective study evaluated local recurrence (LR) and fracture risk in non-spine bone metastases treated with SBRT.
181 lesions in 116 patients are reported. The median dose was 27 Gy (range ...15-40) in 3 fractions (range 1-6). The cumulative incidence of LR was 2.8%, 7.2% and 12.5% at 6 mo, 1 yr and 2 yrs. Fractures occurred in 11 lesions (6%). Radioresistant histology and increasing PTV predicted for LR on univariate analysis, while rib location was associated with control. Increasing PTV remained a significant predictor for LR on multivariate analysis. Univariate predictors of fracture risk included female gender, lytic lesions and poorer KPS. Average CT-approximated L1 trabecular attenuation in patients with fracture was significantly lower than in patients without fracture (112.2 vs. 142.6 Hounsfield units).
In the largest series to date, we report excellent local control for SBRT to non-spine bone metastases and a novel relationship between CT-based bone quality assessment and fracture risk.
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