Phase I Trial of Stereotactic MRI-Guided Online Adaptive Radiation Therapy (SMART) for the Treatment of Oligometastatic Ovarian Cancer.

PURPOSE: Stereotactic body radiation therapy is increasingly used to treat a variety of oligometastatic histologies, but few data exist for ovarian cancer. Ablative stereotactic body radiation therapy dosing is challenging in sites like the abdomen, pelvis, and central thorax due to proximity and motion of organs at risk. A novel radiation delivery method, stereotactic magnetic-resonance-guided online-adaptive radiation therapy (SMART), may improve the therapeutic index of stereotactic body radiation therapy through enhanced soft-tissue visualization, real-time nonionizing imaging, and ability to adapt to the anatomy-of-the-day, with the goal of producing systemic-therapy-free intervals. This phase I trial assessed feasibility, safety, and dosimetric advantage of SMART to treat ovarian oligometastases. METHODS AND MATERIALS: Ten patients with recurrent oligometastatic ovarian cancer underwent SMART for oligometastasis ablation. Initial plans prescribed 35 Gy/5 fractions with goal 95% planning target volume coverage by 95% of prescription, with dose escalation permitted, subject to strict organ-at-risk dose constraints. Daily adaptive planning was used to protect organs-at-risk and/or increase target dose. Feasibility (successful delivery of >80% of fractions in the first on-table attempt) and safety of this approach was evaluated, in addition to efficacy, survival metrics, quality-of-life, prospective timing and dosimetric outcomes. RESULTS: Ten women with seventeen ovarian oligometastases were treated with SMART, and 100% of treatment fractions were successfully delivered. Online adaptive plans were selected at time of treatment for 58% of fractions, due to initial plan violation of organs-at-risk constraints (84% of adapted fractions) or observed opportunity for planning target volume dose escalation (16% of adapted fractions), with a median on-table time of 64 minutes. A single Grade ≥3 acute (within 6 months of SMART) treatment-related toxicity (duodenal ulcer) was observed. Local control at 3 months was 94%; median progression-free survival was 10.9 months. Median Kaplan-Meier estimated systemic-therapy-free survival after radiation completion was 11.5 months, with concomitant quality-of-life improvements. CONCLUSIONS: SMART is feasible and safe for high-dose radiation therapy ablation of ovarian oligometastases of the abdomen, pelvis, and central thorax with minimal toxicity, high rates of local control, and prolonged systemic-therapy-free survival translating into improved quality-of-life.

Tumor Microenvironment as a Regulator of Radiation Therapy: New Insights into Stromal-Mediated Radioresistance.

: A tumor is a complex "organ" composed of malignant cancer cells harboring genetic aberrations surrounded by a stroma comprised of non-malignant cells and an extracellular matrix. Considerable evidence has demonstrated that components of the genetically "normal" tumor stroma contribute to tumor progression and resistance to a wide array of treatment modalities, including radiotherapy. Cancer-associated fibroblasts can promote radioresistance through their secreted factors, contact-mediated signaling, downstream pro-survival signaling pathways, immunomodulatory effects, and cancer stem cell-generating role. The extracellular matrix can govern radiation responsiveness by influencing oxygen availability and controlling the stability and bioavailability of growth factors and cytokines. Immune status regarding the presence of pro- and anti-tumor immune cells can regulate how tumors respond to radiation therapy. Furthermore, stromal cells including endothelial cells and adipocytes can modulate radiosensitivity through their roles in angiogenesis and vasculogenesis, and their secreted adipokines, respectively. Thus, to successfully eradicate cancers, it is important to consider how tumor stroma components interact with and regulate the response to radiation. Detailed knowledge of these interactions will help build a preclinical rationale to support the use of stromal-targeting agents in combination with radiotherapy to increase radiosensitivity.

Single-Institution Phase 1/2 Prospective Clinical Trial of Single-Fraction, High-Gradient Adjuvant Partial-Breast Irradiation for Hormone Sensitive Stage 0-I Breast Cancer.

PURPOSE: We sought to evaluate the feasibility and tolerability of a novel accelerated partial breast irradiation regimen delivered in a single fraction postoperatively. METHODS AND MATERIALS: We enrolled 50 patients with low-risk, hormone-sensitive breast cancer from 2015 to 2018 on a prospective phase 1/2 trial to receive single-fraction, high-gradient partial-breast irradiation (SFHGPBI) 2 to 8 weeks after lumpectomy for node-negative, invasive, or in situ breast cancer. The high gradient was achieved by prescribing 20 Gy to the surgical bed and 5 Gy to the breast tissue within 1 cm of the surgical bed simultaneously in 1 fraction using external beam. RESULTS: The median age was 65 (range, 52-84). Ten patients (20%) had small-volume ductal carcinoma in situ while the remainder had stage I disease. At a median follow-up of 25 months, we evaluated toxicity, patient- and physician-reported cosmesis, patient-reported quality of life (QOL), and initial tumor control. There was no Common Terminology Criteria for Adverse Events v4.0 grade 3+ toxicity. Only 34% of patients experienced grade 1 erythema. Good-to-excellent pretreatment cosmesis was present in 100% and 98% per physicians and patients, respectively, and did not change post-SFHGPBI. Quantitative cosmesis by percentage of breast retraction assessment significantly improved over time during the post-SFHGPBI period per mixed repeated measures modeling (P = .0026). QOL per European Organization for Research and Treatment of Cancer QOL Questionnaires C30 and BR-23 did not decline other than temporarily in the systemic therapy effects and hair loss domains, both of which returned to pretreatment values. There was 1 noninvasive in-breast recurrence in a separate untreated quadrant 18 months post-SFHGPBI and 1 isolated axillary recurrence 30 months post-SFHGPBI, both salvaged successfully. There were no distant recurrences or cancer-related deaths observed. CONCLUSIONS: Accelerated partial-breast irradiation delivered in a single fraction postoperatively using external beam techniques is a novel, feasible, well-tolerated regimen. SFHGPBI does not adversely affect cosmesis or QOL as reported by both physicians and patients. Initial tumor control rates are excellent, with longer follow-up required to confirm efficacy.

Activity of CEP-9722, a poly (ADP-ribose) polymerase inhibitor, in urothelial carcinoma correlates inversely with homologous recombination repair response to DNA damage.

As loss of DNA-repair proteins is common in urothelial carcinoma (UC), a rationale can be made to evaluate the activity of poly (ADP-ribose) polymerase (PARP) inhibitors to exploit synthetic lethality. We aimed to preclinically evaluate a PARP inhibitor, CEP-9722, and its active metabolite, CEP-8983, in UC. The activity of CEP-8983 was evaluated using a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay against human UC cell lines. Flow cytometry, COMET assay, and western blot were performed to assess apoptosis, DNA damage, and DNA-repair proteins, respectively. RT4 xenografts received placebo or CEP-9722 (100 or 200 mg/kg/day) orally. Xenografts were subjected to immunohistochemistry for apoptosis [cleaved caspase (cc)-3] and angiogenesis (CD31). CEP-8983 (1 µmol/l) reduced the viability of RT4 and T24 cells by 20%, but did not reduce the viability of 5637 and TCC-SUP cells. Apoptosis and necrosis occurred in 9.7 and 9.1% of RT4 and 5637 cells, respectively. RT4 cells showed greater DNA damage compared with 5637 cells. Increased DNA damage occurred with combination versus CEP-8983 or cisplatin alone in RT4 and 5637 cells. T24 and RT4 showed the least RAD51 foci 8 h following radiation, whereas TCC-SUP and 5637 robustly induced RAD51 foci. CEP-9722 showed dose-dependent antitumor activity in RT4 xenografts; 200 mg/kg daily was better than control (P=0.04) and 100 mg/kg was not (P=0.26). Immunohistochemistry of xenografts showed a significant increase in cc-3 and decrease in CD31 with both doses (P<0.05). Biomarker-driven evaluation of PARP inhibitors in UC is justified as the activity of CEP-9722 correlated inversely with homologous recombination repair response to DNA damage.

PARP-1: Friend or Foe of DNA Damage and Repair in Tumorigenesis?

Oxidative stress induced by reactive oxygen species can result in DNA damage within cells and subsequently increase risk for carcinogenesis. This may be averted by repair of DNA damage through the base or nucleotide excision repair (BER/NER) pathways. PARP, a BER protein, is known for its role in DNA-repair. However, multiple lesions can occur within a small range of DNA, known as oxidative clustered DNA lesions (OCDLs), which are difficult to repair and may lead to the more severe DNA double-strand break (DSB). Inefficient DSB repair can then result in increased mutagenesis and neoplastic transformation. OCDLs occur more frequently within a variety of tumor tissues. Interestingly, PARP is highly expressed in several human cancers. Additionally, chronic inflammation may contribute to tumorigenesis through ROS-induced DNA damage. Furthermore, PARP can modulate inflammation through interaction with NFκB and regulating the expression of inflammatory signaling molecules. Thus, the upregulation of PARP may present a double-edged sword. PARP is needed to repair ROS-induced DNA lesions, but PARP expression may lead to increased inflammation via upregulation of NFκB signaling. Here, we discuss the role of PARP in the repair of oxidative damage versus the formation of OCDLs and speculate on the feasibility of PARP inhibition for the treatment and prevention of cancers by exploiting its role in inflammation.

Synthetic lethal interactions between EGFR and PARP inhibition in human triple negative breast cancer cells.

Few therapeutic options exist for the highly aggressive triple negative breast cancers (TNBCs). In this study, we report that a contextual synthetic lethality can be achieved both in vitro and in vivo with combined EGFR and PARP inhibition with lapatinib and ABT-888, respectively. The mechanism involves a transient DNA double strand break repair deficit induced by lapatinib and subsequent activation of the intrinsic pathway of apoptosis. Further dissection of the mechanism reveals that EGFR and BRCA1 can be found in the same protein complex, which is reduced by lapatinib. Interestingly, lapatinib also increases cytosolic BRCA1 and EGFR, away from their nuclear DNA repair substrates. Taken together, these results reveal a novel regulation of homologous recombination repair involving EGFR and BRCA1 interaction and alteration of subcellular localization. Additionally, a contextual synthetic lethality may exist between combined EGFR and PARP inhibitors.

Kinomic profiling approach identifies Trk as a novel radiation modulator.

BACKGROUND: Ionizing radiation treatment is used in over half of all cancer patients, thus determining the mechanisms of response or resistance is critical for the development of novel treatment approaches. MATERIALS AND METHODS: In this report, we utilize a high-content peptide array platform that performs multiplex kinase assays with real-time kinetic readout to investigate the mechanism of radiation response in vascular endothelial cells. We applied this technology to irradiated human umbilical vein endothelial cells (HUVEC). RESULTS: We identified 49 specific tyrosine phosphopeptides that were differentially affected by irradiation over a time course of 1h. In one example, the Tropomyosin receptor kinase (Trk) family members, TrkA and TrkB, showed transient activation between 2 and 15 min following irradiation. When we targeted TrkA and TrkB using small molecule inhibitors, HUVEC were protected from radiation damage. Conversely, stimulation of TrkA using gambogic amide promoted radiation enhancement. CONCLUSIONS: Thus, we show that our approach not only can identify rapid changes in kinase activity but also identify novel targets such as TrkA. TrkA inhibition resulted in radioprotection that correlated with enhanced repair of radiation-induced damage while TrkA stimulation by gambogic amide produced radiation sensitization.

Work stress, burnout, and social and personal resources among direct care workers.

Work stress is endemic among direct care workers (DCWs) who serve people with intellectual and developmental disabilities. Social resources, such as work social support, and personal resources, such as an internal locus of control, may help DCWs perceive work overload and other work-related stressors as less threatening and galvanize them to cope more effectively to prevent burnout. However, little is known about what resources are effective for coping with what types of work stress. Thus, we examined how work stress and social and personal resources are associated with burnout for DCWs. We conducted a survey of DCWs (n = 323) from five community-based organizations that provide residential, vocational, and personal care services for adults with intellectual and developmental disabilities. Participants completed a self-administered survey about their perceptions of work stress, work social support, locus of control, and burnout relative to their daily work routine. We conducted multiple regression analysis to test both the main and interaction effects of work stress and resources with respect to burnout. Work stress, specifically work overload, limited participation decision-making, and client disability care, was positively associated with burnout (p < .001). The association between work social support and burnout depended on the levels of work overload (p < .05), and the association between locus of control and burnout depended on the levels of work overload (p < .05) and participation in decision-making (p < .05). Whether work social support and locus of control make a difference depends on the kinds and the levels of work stressors. The findings underscore the importance of strong work-based social support networks and stress management resources for DCWs.

Barrier removal in increasing physical activity levels in obese African American women with disabilities.

BACKGROUND: This pilot study examined the effectiveness of a telephone-based intervention to increase physical activity in obese African American women with mobility disabilities by targeting the removal of barriers to participation. METHODS: Severely obese (mean body mass index [BMI] = 49.1 kg.m²) African American women (n = 33) with mobility disabilities completed a 6-month telephone-based physical activity coaching intervention. RESULTS: The major environmental/facility barriers at preintervention were cost of the program (66.7%), lack of transportation (48.5%), not aware of fitness center in the area (45.5%), and lack of accessible facilities (45.5%). The major personal barriers were pain (63.6%), don't know how to exercise (45.5%), health concerns (39.4%), don't know where to exercise (39.4%), and lack of energy (36.4%). Despite only two personal barriers being significantly lower at posttest (don't know where to exercise and don't know how to exercise) (p < 0.01), total exercise time increased from < 6 minutes/day to 27 minutes/day at posttest (p < 0.001), and total physical activity time (structured exercise, leisure, indoor and outdoor household activity) increased from 26 minutes/day to 89 minutes/day at posttest (p < 0.001). CONCLUSIONS: Interventions aimed at increasing physical activity participation among obese African American women with mobility disabilities should start with increasing their awareness/knowledge on where and how to exercise. Other reported barriers (e.g., cost, transportation, finding an accessible facility, health concerns, pain) may not be as critical to alter/remove as identifying where participants can exercise (i.e., home, outdoors, gym) and providing them with a variety of routines that can be performed safely in their desired setting.

Pharmacological characterization and appetite suppressive properties of BMS-193885, a novel and selective neuropeptide Y(1) receptor antagonist.

Treatment of obesity is still a large unmet medical need. Neuropeptide Y is the most potent orexigenic peptide in the animal kingdom. Its five cloned G-protein couple receptors are all implicated in the regulation of energy homeostasis evidenced by overexpression or deletion of neuropeptide Y or its receptors. Neuropeptide Y most likely exerts its orexigenic activity via the neuropeptide Y(1) and neuropeptide Y(5) receptors, although the involvement of the neuropeptide Y(2) and neuropeptide Y(4) receptors are also gaining importance. The lack of potent, selective, and brain penetrable pharmacologic agents at these receptors made our understanding of the modulation of food intake by neuropeptide Y-ergic agents elusive. BMS-193885 (1,4-dihydro-[3-[[[[3-[4-(3-methoxyphenyl)-1-piperidinyl]propyl]amino] carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acid, dimethyl ester) is a potent and selective neuropeptide Y(1) receptor antagonist. BMS-193885 has 3.3 nM affinity at the neuropeptide Y(1) receptor, acting competitively at the neuropeptide Y binding site. BMS-193885 increased the K(d) of [(125)I]PeptideYY from 0.35 nM to 0.65 nM without changing the B(max) (0.16 pmol/mg of protein) in SK-N-MC cells that endogenously express the neuropeptide Y(1) receptor. It is also found to be a full antagonist with an apparent K(b) of 4.5 nM measured by reversal of forskolin (FK)-stimulated inhibition of cAMP production by neuropeptide Y. Pharmacological profiling showed that BMS-193885 has no appreciable affinity at the other neuropeptide Y receptors, and is also 200-fold less potent at the alpha(2) adrenergic receptor. Testing the compound in a panel of 70 G-protein coupled receptors and ion channels resulted in at least 200-fold or greater selectivity, with the exception of the sigma(1) receptor, where the selectivity was 100-fold. When administered intracerebroventricularly or directly into the paraventricular nucleus of the hypothalamus, it blocked neuropeptide Y-induced food intake in rats. Intraperitoneal administration of BMS-193885 (10 mg/kg) also reduced one-hour neuropeptide Y-induced food intake in satiated rats, as well as spontaneous overnight food consumption. Chronic administration of BMS-193885 (10 mg/kg) i.p. for 44 days significantly reduced food intake and the rate of body weight gain compared to vehicle treated control without developing tolerance or affecting water intake. These results provide supporting evidence that BMS-193885 reduces food intake and body weight via inhibition of the central neuropeptide Y(1) receptor. BMS-193885 has no significant effect of locomotor activity up to 20 mg/kg dose after 1 h of treatment. It also showed no activity in the elevated plus maze when tested after i.p. and i.c.v. administration, indicating that reduction of food intake is unrelated to anxious behavior. BMS-193885 has good systemic bioavailability and brain penetration, but lacks oral bioavailability. The compound had no serious cardiovascular adverse effect in rats and dogs up to 30 and 10 mg/kg dose, respectively, when dosed intravenously. These data demonstrate that BMS-193885 is a potent, selective, brain penetrant Y(1) receptor antagonist that reduces food intake and body weight in animal models of obesity both after acute and chronic administration. Taken together the data suggest that a potent and selective neuropeptide Y(1) receptor antagonist might be an efficacious treatment for obesity in humans.

Dihydropyridine neuropeptide Y Y(1) receptor antagonists.

Dihydropyridine 5a was found to be an inhibitor of neuropeptide Y(1) binding in a high throughput (125)I-PYY screening assay. Structure-activity studies around certain portions of the dihydropyridine chemotype identified BMS-193885 (6e) as a potent and selective Y(1) receptor antagonist. In a forskolin-stimulated c-AMP production assay using CHO cells expressing the human Y(1) receptor, 6e demonstrated full functional antagonism (K(b)=4.5 nM). Compound 6e inhibited NPY-induced feeding in satiated rats when dosed at 3.0 and 10.0 mg/kg (ip), and also decreased spontaneous overnight food consumption in rats at doses of 10 and 20 mg/kg (ip).