Identifying new actions of estrogen receptor targetable with small molecules

Estrogens, acting via estrogen receptor α (ERα), stimulate the proliferation and metastatic potential of breast cancers, and likely some ovarian, endometrial, and cervical cancers. Endocrine therapy targeting these cancers often leads to development of resistance. Ovarian cancers do not respond to endocrine therapy. The presence of ERα in many resistant tumors suggested the existence of additional modes of ERα action that could be targeted with small molecule biomodulators. To identify new small molecule inhibitors that target the estrogen-ERα axis in cancer cells resistant to current therapies, we developed and implemented an unbiased pathway-directed screen of ~150,000 small molecules. Using screening and functional validation, I identified BHPI, a potent non-competitive small molecule ERα inhibitor. At 100 nM, BHPI completely inhibited estrogen-induced proliferation in ERα containing breast, ovarian and endometrial cancer cells with no effect at 10,000 nM in counterpart ERα negative cells. BHPI effectively targets cancer cells that no longer depend on estrogens for growth, kills drug-resistant breast and ovarian cancer cells, and restores paclitaxel sensitivity to multi-drug resistant cancer cells. In a mouse xenograft, BHPI at 15 mg/kg daily for 10 days induced rapid and substantial regression of 48/52 large tumors and was not toxic. BHPI’s effectiveness in a broad range of ERα-containing breast, ovarian and endometrial cancer cells is due to its ability to target the endoplasmic reticulum stress sensor pathway, the unfolded protein response (UPR). In ERα positive cancer cells, BHPI opens the endoplasmic reticulum IP3R calcium channel, triggering efflux of calcium into the cytosol, strongly activating all three arms of the UPR. BHPI activates the PERK arm of the UPR, which leads to phosphorylation of eukaryotic initiation factor 2α (eIF2α), and potent inhibition of protein synthesis. To restore endoplasmic reticulum calcium, calcium-ATPase pumps are activated, but the calcium rapidly leaks back out through the open IP3R channel, creating an ATP-depleting futile cycle. ATP depletion activates the energy sensor, AMPK. The influx of calcium into the cytosol leads to phosphorylation and inactivation of eukaryotic elongation factor 2 (eEF2), inhibiting the elongation step of protein synthesis. Inhibiting protein synthesis at a second site prevents synthesis of chaperones and other proteins that normally resolve UPR stress. BHPI kills ERα positive cancer cells by triggering a lethal cascade encompassing sustained activation of the UPR, persistent inhibition of protein synthesis, and depletion of ATP stores. BHPI selectively targets the UPR in ERα positive cancer cells by distorting a previously unknown ability of estrogen-ERα to stimulate a weak and transient UPR activation that protects cancer cells from subsequent stress. This anticipatory activation of the UPR by estrogen-ERα is essential for estrogen-ERα-induced gene expression and cell proliferation, and is a new paradigm by which estrogens promote therapy-resistance and tumor progression. Bioinformatic analysis of data from ≈1,000 ERα positive breast tumors shows that estrogen-ERα and UPR activity become elevated during tumor development and that a UPR gene signature is a powerful new prognostic biomarker predictive of resistance to tamoxifen therapy, time to relapse, and overall survival. We employed a novel approach to identifying new pathways and cancer biomarkers in which unbiased high throughput screening is used to “interrogate the cell”. For a well-studied protein, such as ERα, it was unclear whether this approach could identify new pathways and biomarkers and promising new drug candidates. These studies demonstrate the potential of small molecules identified through targeted cell-based screening to reveal and validate new pathways of action, therapeutic drug targets, and small molecule therapeutic candidates; even in a system as intensively studied as ERα positive breast cancer

Heart sparing radiotherapy techniques in breast cancer: A focus on deep inspiration breath hold

Adjuvant radiation therapy is a critical component of breast cancer management. However, when breast cancer patients receive incidental radiation to the heart, there is an increased risk of cardiac disease and mortality. This is most common for patients with left-sided breast cancers and those receiving nodal irradiation as part of treatment. The overall risk of cardiac toxicity increases 4-16% with each Gray increase in mean heart radiation dose, with data suggesting that no lower limit exists which would eliminate cardiac risk entirely. Radiation techniques have improved over time, leading to lower cardiac radiation exposure than in the past. This decline is expected to reduce the incidence of radiation-induced heart dysfunction in patients. Deep inspiration breath hold (DIBH) is one such technique that was developed to reduce the risk of cardiac death and coronary events. DIBH is a non-invasive approach that capitalizes on the natural physiology of the respiratory cycle to increase the distance between the heart and the therapeutic target throughout the course of radiation therapy. DIBH has been shown to decrease the mean incidental radiation doses to the heart and left anterior descending coronary artery by approximately 20-70%. In this review, we summarize different techniques for DIBH and discuss recent data on this technique

The novel use of a commercially available video-conference platform to facilitate multidisciplinary target volume review and delineation for skull-base radiation therapy during the coronavirus disease 2019 pandemic

Multidisciplinary involvement in radiation therapy (RT) treatment planning is currently underused. A radiation oncologist sought input for generating target contours from a neuro-radiologist (NR) and otolaryngologist (OL) for 3 patients requiring skull-base RT during the coronavirus disease 2019 pandemic. A Health Insurance Portability and Accountability Act compliant virtual meeting between the radiation oncologist, NR, and OL was arranged. Involvement of the OL and NR led to significant changes in the clinical target volume for all patients. Our experience highlights the feasibility of using commercially available video-conference platforms for multidisciplinary target volume delineation for complex RT cases. Further applications include interdisciplinary contour review for RT cases requiring special expertise and joint attending/resident physician contour review for resident education. The video-conference platform technology has demonstrated benefit during the coronavirus disease 2019 pandemic, and we believe it will remain an integral component of our field moving forward

The association of radiation dose with overall survival for patients treated with prostate stereotactic body radiation therapy

Introduction Stereotactic body radiation therapy (SBRT) for prostate adenocarcinoma (PCa) has demonstrated excellent biochemical recurrence-free survival, with studies showing improved BRFS with higher-dose SBRT. However, current studies have been underpowered to evaluate the relationship of SBRT dose to overall survival (OS). In this retrospective study using the National Cancer Database (NCDB), we hypothesize that, given the low alpha/beta ratio of PCa, a relatively small increase in the dose-per-fraction would be associated with improved survival outcomes for intermediate-risk PCa (IR-PCa) comparing 36.25 Gy/5 fx [biologically equivalent dose (BEDα/β = 1.5 = 211.46 Gy vs. 35 Gy (BED1.5 = 198.33 Gy)]. Materials and methods We queried records from the NCDB from 2005 to 2015 for men receiving prostate SBRT for IR-PCa (n=2673). 82% were treated using either 35 Gy/5 fx or 36.25 Gy/5 fx. We compared OS in men receiving 35 Gy versus 36.25 Gy. Inverse probability of treatment weighting (IPTW) was used to adjust for covariable imbalances. Unweighted- and weighted-multivariable analysis (MVA) using Cox regression was used to compare OS hazard ratios, accounting for age, race, Charlson-Deyo comorbidity score, treatment facility type, prostate-specific antigen (PSA), clinical T-stage, Gleason Score, and use of androgen deprivation therapy (ADT). Kaplan-Meier analysis was performed. Results Seven hundred and eighty men (35%) were treated with 35 Gy/5 fx and 1434 men (65%) were treated with 36.25 Gy/5 fx (n=2214). Compared to 35 Gy, treatment with 36.25 Gy was associated with significantly improved OS (hazard ratio [HR]: 0.61 [95% CI: 0.43-0.89]

Intrinsic tumor resistance to CAR T cells is a dynamic transcriptional state that is exploitable with low-dose radiation

Chimeric antigen receptor (CAR) T-cell therapy represents a major advancement for hematologic malignancies, with some patients achieving long-term remission. However, the majority of treated patients still die of their disease. A consistent predictor of response is tumor quantity, wherein a higher disease burden before CAR T-cell therapy portends a worse prognosis. Focal radiation to bulky sites of the disease can decrease tumor quantity before CAR T-cell therapy, but whether this strategy improves survival is unknown. We find that substantially reducing systemic tumor quantity using high-dose radiation to areas of bulky disease, which is commonly done clinically, is less impactful on overall survival in mice achieved by CAR T cells than targeting all sites of disease with low-dose total tumor irradiation (TTI) before CAR T-cell therapy. This finding highlights another predictor of response, tumor quality, the intrinsic resistance of an individual patient\u27s tumor cells to CAR T-cell killing. Little is known about whether or how an individual tumor\u27s intrinsic resistance may change under different circumstances. We find a transcriptional death receptor score that reflects a tumor\u27s intrinsic sensitivity to CAR T cells can be temporarily increased by low-dose TTI, and the timing of this transcriptional change correlates with improved in vivo leukemia control by an otherwise limited number of CAR T cells. This suggests an actionable method for potentially improving outcomes in patients predicted to respond poorly to this promising therapy and highlights that intrinsic tumor attributes may be equally or more important predictors of CAR T-cell response as tumor burden

CT-based online adaptive radiotherapy improves target coverage and organ at risk (OAR) avoidance in stereotactic body radiation therapy (SBRT) for prostate cancer

INTRODUCTION: Stereotactic body radiation therapy (SBRT) is an emerging treatment modality for clinically localized prostate cancer (PCa). Online daily adaptive radiotherapy (ART) could potentially improve the therapeutic ratio of prostate SBRT by accounting for inter-fraction variation in target and OAR volumes. To our knowledge, no group has evaluated the clinical utility of a novel AI-augmented CT-based ART system for prostate SBRT. In this study we hypothesized that adaptive prostate SBRT plans would result in improved target coverage and lower dose to OARs in comparison to unadapted treatment plans. METHODS: Seven patients with favorable intermediate to oligometastatic PCa treated with 5-fx prostate adaptive SBRT were retrospectively reviewed. Patients were treated with 3625 cGy to the prostate and seminal vesicles. 6 patients additionally received 2500 cGy to the pelvic nodes, 5 patients underwent a boost to 4000 cGy to the prostate. For each fraction, a CBCT was acquired and OARs (rectum, bladder, bowel, sigmoid, femurs) were segmented/deformed using AI. CTVs were rigidly registered. Volumes were adjusted manually and PTV expansions added. Adaptive treatment plans were developed based on the contoured targets and OARs and dose to these volumes for the adapted vs. initial plans were compared for each fraction. V100 and the D0.03 cc between scheduled and adapted treatment plans were compared using a Student\u27s RESULTS: Seven patients completed 35 Fx\u27s of adaptive RT. Daily adaptation resulted in a statistically significant mean improvement in PTV V100 for all targets: [21.4 % ± 4.3 % for PTV 4000 (p \u3c 0.0001); 8.7 % ± 1.1 % for PTV 3625 (p \u3c 0.0001); and 11.5 % ± 3.1 % for PTV 2500 (p = 0.0013)]. Mean rectal D0.03 was significantly reduced by 38.8 cGy ± 5.95 cGy (p \u3c 0.0001) per fraction (194 cGy/5 fractions) compared to the initial plans. There was a modest increase in bladder dose of 10.9 cGy ± 4.93 cGy per fraction (p = 0.0424) for the adaptive plans. The adaptive plans met bladder constraints for every fraction. There were no statistically significant differences between sigmoid or bowel dose for adapted vs. initial plans. No patients experienced acute CTCAE grade ≥ 3 GI/GU adverse events (median F/U 9.5 months). All statistically significant differences were maintained in the presence and absence of rectal hydrogel spacer (p \u3c 0.05). CONCLUSIONS: CT-based online adaptive SBRT resulted in statistically significant and clinically meaningful improvements in PTV coverage and D0.03 cc dose to the rectum. A trial evaluating CT adaptive whole-pelvis prostate SBRT is underway