Locally Advanced Lung Cancer.

Consolidation immunotherapy after concurrent chemoradiation has improved five-year survival rates in unresectable, locally advanced lung cancer, but disease progression and treatment personalization remain challenges. New treatment approaches with concurrent immunotherapy and consolidative novel agents are being investigated and show promising efficacy data, but at the risk of additive toxicity. Patients with PD-L1 negative tumors, oncogenic driver mutations, intolerable toxicity, or limited performance status continue to require innovative therapies. This review summarizes historical data that galvanized new research efforts, as well as ongoing clinical trials that address the challenges of current therapeutic approaches for unresectable, locally advanced lung cancer.

Ym155 localizes to the mitochondria leading to mitochondria dysfunction and activation of AMPK that inhibits BMP signaling in lung cancer cells.

The imidazolium compound Ym155 was first reported to be a survivin inhibitor. Ym155 potently induces cell death of many types of cancer cells in preclinical studies. However, in phase II clinical trials Ym155 failed to demonstrate a significant benefit. Studies have suggested that the cytotoxic effects of Ym155 in cancer cells are not mediated by the inhibition of survivin. Understanding the mechanism by which Ym155 induces cell death would provide important insight how to improve its efficacy as a cancer therapeutic. We demonstrate a novel mechanism by which Ym155 induces cell death by localizing to the mitochondria causing mitochondrial dysfunction. Our studies suggest that Ym155 binds mitochondrial DNA leading to a decrease in oxidative phosphorylation, decrease in TCA cycle intermediates, and an increase in mitochondrial permeability. Furthermore, we show that mitochondrial stress induced by Ym155 and other mitochondrial inhibitors activates AMP-activated kinase leading to the downregulation to bone morphogenetic protein (BMP) signaling. We provide first evidence that Ym155 initiates cell death by disrupting mitochondrial function.

Bone morphogenetic protein signaling regulation of AMPK and PI3K in lung cancer cells and C. elegans.

BACKGROUND: Bone morphogenetic protein (BMP) is a phylogenetically conserved signaling pathway required for development that is aberrantly expressed in several age-related diseases including cancer, Alzheimer's disease, obesity, and cardiovascular disease. Aberrant BMP signaling in mice leads to obesity, suggesting it may alter normal metabolism. The role of BMP signaling regulating cancer metabolism is not known. METHODS: To examine BMP regulation of metabolism, C. elegans harboring BMP gain-of-function (gof) and loss-of-function (lof) mutations were examined for changes in activity of catabolic and anabolic metabolism utilizing Western blot analysis and fluorescent reporters. AMP activated kinase (AMPK) gof and lof mutants were used to examine AMPK regulation of BMP signaling. H1299 (LKB1 wild-type), A549 (LKB1 lof), and A549-LKB1 (LKB1 restored) lung cancer cell lines were used to study BMP regulation of catabolic and anabolic metabolism. Studies were done using recombinant BMP ligands to activate BMP signaling, and BMP receptor specific inhibitors and siRNA to inhibit signaling. RESULTS: BMP signaling in both C. elegans and cancer cells is responsive to nutrient conditions. In both C. elegans and lung cancer cell lines BMP suppressed AMPK, the master regulator of catabolism, while activating PI3K, a regulator of anabolism. In lung cancer cells, inhibition of BMP signaling by siRNA or small molecules increased AMPK activity, and this increase was mediated by activation of LKB1. BMP2 ligand suppressed AMPK activation during starvation. BMP2 ligand decreased expression of TCA cycle intermediates and non-essential amino acids in H1299 cells. Furthermore, we show that BMP activation of PI3K is mediated through BMP type II receptor. We also observed feedback signaling, as AMPK suppressed BMP signaling, whereas PI3K increased BMP signaling. CONCLUSION: These studies show that BMP signaling suppresses catabolic metabolism and stimulates anabolic metabolism. We identified feedback mechanisms where catabolic induced signaling mediated by AMPK negatively regulates BMP signaling, whereas anabolic signaling produces a positive feedback regulation of BMP signing through Akt. These mechanisms were conserved in both lung cancer cells and C. elegans. These studies suggest that aberrant BMP signaling causes dysregulation of metabolism that is a potential mechanism by which BMP promotes survival of cancer cells.

Bone morphogenetic protein inhibitors and mitochondria targeting agents synergistically induce apoptosis-inducing factor (AIF) caspase-independent cell death in lung cancer cells.

BACKGROUND: Bone morphogenetic proteins (BMP) are evolutionarily conserved morphogens that are reactivated in lung carcinomas. In lung cancer cells, BMP signaling suppresses AMP activated kinase (AMPK) by inhibiting LKB1. AMPK is activated by mitochondrial stress that inhibits ATP production, which is enhanced 100-fold when phosphorylated by LKB1. Activated AMPK can promote survival of cancer cells but its "hyperactivation" induces cell death. The studies here reveal novel cell death mechanisms induced by BMP inhibitors, together with agents targeting the mitochondria, which involves the "hyperactivation" of AMPK. METHODS: This study examines the synergistic effects of two BMP inhibitors together with mitochondrial targeting agents phenformin and Ym155, on cell death of lung cancer cells expressing LKB1 (H1299), LKB1 null (A549), and A549 cells transfected with LKB1 (A549-LKB1). Cell death mechanisms evaluated were the activation of caspases and the nuclear localization of apoptosis inducing factor (AIF). A769662 was used to allosterically activate AMPK. Knockdown of BMPR2 and LKB1 using siRNA was used to examine their effects on nuclear localization of AMPK. Validation studies were performed on five passage zero primary NSCLC. RESULTS: Both BMP inhibitors synergistically suppressed growth when combined with Ym155 or phenformin in cells expressing LKB1. The combination of BMP inhibitors with mitochondrial targeting agents enhanced the activation of AMPK in lung cancer cells expressing LKB1. Allosteric activation of AMPK with A769662 induced cell death in both H1299 and A549 cells. Cell death induced by the combination of BMP inhibitors and mitochondrial-targeting agents did not activate caspases. The combination of drugs induced nuclear localization of AIF in cells expressing LKB1, which was attenuated by knockdown of LKB1. Knockdown of BMPR2 together with Ym155 increased nuclear localization of AIF. Combination therapy also enhanced cell death and AIF nuclear localization in primary NSCLC. CONCLUSIONS: These studies demonstrate that inhibition of BMP signaling together with mitochondrial targeting agents induce AIF caspase-independent cell death, which involves the "hyperactivation" of AMPK. AIF caspase-independent cell death is an evolutionarily conserved cell death pathway that is infrequently studied in cancer. These studies provide novel insight into mechanisms inducing AIF caspase-independent cell death in cancer cells using BMP inhibitors. Video Abstract.

Bone morphogenetic protein receptor inhibitors suppress the growth of glioblastoma cells.

Glioblastomas (GBMs) are aggressive brain tumors that are resistant to chemotherapy and radiation. Bone morphogenetic protein (BMP) ligand BMP4 is being examined as a potential therapeutic for GBMs because it induces differentiation of cancer stem cells (CSCs) to an astrocyte phenotype. ID1 is reported to promote self-renewal and inhibit CSC differentiation. In most cancers, ID1 is transcriptionally upregulated by BMP4 promoting invasion and stemness. This conflicting data bring into question whether BMP signaling is growth suppressive or growth promoting in GBMs. We utilized BMP inhibitors DMH1, JL5, and Ym155 to examine the role of BMP signaling on the growth of GBMs. DMH1 targets BMP type 1 receptors whereas JL5 inhibits both the type 1 and type 2 BMP receptors. Ym155 does not bind the BMP receptors but rather inhibits BMP signaling by inducing the degradation of BMPR2. We show that JL5, DMH1, and Ym155 decreased the expression of ID1 in SD2 and U87 cells. JL5 and Ym155 also decreased the expression of BMPR2 and its downstream target inhibitor of apoptosis protein XIAP. JL5 treatment resulted in significant cell death and suppressed self-renewal to a greater extent than that induced by BMP4 ligand. The lysosome inhibitor chloroquine increases the localization of BMPR2 to the plasma membrane enhancing JL5-induced downregulation of ID1 and cell death in SD2 cells. We show that BMP signaling is growth promoting in GBMs. These studies suggest the need for development of BMP inhibitors and evaluation as potential therapeutic for GBMs.

Bone morphogenetic protein receptor 2 inhibition destabilizes microtubules promoting the activation of lysosomes and cell death of lung cancer cells.

BACKGROUND: Recent studies have shown that bone morphogenetic protein receptor 2 (BMPR2) regulates cell survival signaling events in cancer cells independent of the BMP type 1 receptor (BMPR1) or the Smad-1/5 transcription factor. Mutations in BMPR2 trafficking proteins leads to overactive BMP signaling, which leads to neurological diseases caused by BMPR2 stabilization of the microtubules. It is not known whether BMPR2 regulates the microtubules in cancer cells and what effect this has on cell survival. It is also not known whether alterations in BMPR2 trafficking effects activity and response to BMPR2 inhibitors. METHODS: We utilized BMPR2 siRNA and the BMP receptor inhibitors JL5 and Ym155, which decrease BMPR2 signaling and cause its mislocalization to the cytoplasm. Using the JL5 resistant MDA-MD-468 cell line and sensitive lung cancer cell lines, we examined the effects of BMPR2 inhibition on BMPR2 mislocalization to the cytoplasm, microtubule destabilization, lysosome activation and cell survival. RESULTS: We show that the inhibition of BMPR2 destabilizes the microtubules. Destabilization of the microtubules leads to the activation of the lysosomes. Activated lysosomes further decreases BMPR2 signaling by causing it to mislocalizated to the cytoplasm and/or lysosome for degradation. Inhibition of the lysosomes with chloroquine attenuates BMPR2 trafficking to the lysosome and cell death induced by BMPR2 inhibitors. Furthermore, in MDA-MD-468 cells that are resistant to JL5 induced cell death, BMPR2 was predominately located in the cytoplasm. BMPR2 failed to localize to the cytoplasm and/or lysosome following treatment with JL5 and did not destabilize the microtubules or activate the lysosomes. CONCLUSIONS: These studies reveal that the inhibition of BMPR2 destabilizes the microtubules promoting cell death of cancer cells that involves the activation of the lysosomes. Resistance to small molecules targeting BMPR2 may occur if the BMPR2 is localized predominantly to the cytoplasm and/or fails to localize to the lysosome for degradation. Video Abstract.

Combining radiation therapy and immunotherapy for lung cancers: a narrative review.

Lung cancer remains the leading cause of cancer morbidity and mortality worldwide among both men and women. While surgical resection remains the standard of care for early stage NSCLC, chemoradiation has been a mainstay of treatment for locally advanced non-small-cell lung cancer (LA-NSCLC) patients for decades. Consolidation immunotherapy has improved survival in this subset of patients after conventional chemoradiation, and has emerged as the new standard. The synergy between immunotherapy and radiation, as well as ongoing research on the effects of radiation on the immune system, allows for the exploration of new avenues in the treatment of LA-NSCLC. In addition to the use of durvalumab as consolidative systemic therapy after concurrent chemoradiotherapy for Stage III NSCLC, other combination regimens have been shown to be effective in various disease stages in preclinical and clinical studies. These regimens include CTLA-4 and PD/PDL-1 checkpoint inhibitors combined with radiation treatment. While these combined regimens have demonstrated efficacy, they are not without toxicity, and require additional evaluation when combined with radiation. In this review, we have summarized the immunostimulatory and immunosuppressive effects of radiation therapy. We also evaluate the current evidence and ongoing research supporting the combination of radiotherapy and immunotherapy across early to LA-NSCLC.

Tumor volume reduction evaluated by cone beam computed tomography during stereotactic body radiotherapy for early stage non-small cell lung cancer.

BACKGROUND: We hypothesized that significant tumor volume reduction (TVR) occurs over the course of stereotactic body radiotherapy (SBRT) for early stage non-small cell lung cancer (NSCLC), and that TVR correlates with clinical outcomes. METHODS: We conducted a retrospective review of patients treated with SBRT for early stage NSCLC across two academic centers. For each patient, we contoured the tumor volume (TV) on cone beam computed tomography (CBCT) images obtained before each treatment fraction. We then calculated TVR based on the TV from the first and last days of treatment. We used log-rank tests to quantify differences in overall survival (OS), progression-free survival (PFS) and recurrence based on TVR. RESULTS: Data from 69 patients and a total of 73 treated tumors were analyzed. The median follow-up for survivors was 51.8 months (range, 6.9 to 80.0 months). The median TVR for the cohort was 10.1% (range, -5.7% to 43.5%). There was no significant difference in either OS (median 33.4 vs. 29.1 months, P=0.79) or PFS (median 26.3 vs. 12.3 months, P=0.43) for those with high TVRs (≥10.1%) vs. low TVRs (<10.1%), respectively. There was a trend toward superior 2-year PFS in the high TVR group (52.2% vs. 36.7%, P=0.062), but this effect diminished on longer follow-up (4-year PFS 31.9% vs. 26.7%, P=0.15). No associations were observed between TVR and local, regional or distant recurrence. CONCLUSIONS: We were not able to demonstrate that TVR is a reliable predictive imaging marker for stage I/II NSCLC treated with SBRT. Future studies with larger sample sizes are needed to clarify a potential relationship between TVR and early outcomes.

Surgical and endoscopic management of a pericardioesophageal fistula after radiofrequency pulmonary vein isolation.

INTRODUCTION: The most feared complication of pulmonary vein isolation (PVI) is an atrioesophageal fistula (AEF). While rare (0.1-0.25%), primary surgical closure (as opposed to esophageal stenting) is associated with lower mortality. Pericardioesophageal fistula (PEF) may present prior to fistulization into the atrium. Unfortunately, data on the optimal management of PEFs are lacking. CASE REPORT: Seventy-one-year-old male with AF presented with chest pain 3 weeks after radiofrequency PVI. Computed tomography angiography (CTA) chest and echocardiogram showed pneumopericardium. Barium esophagram showed extravasation from esophagus into the pericardium without connection to the left atrium. Sternotomy with mediastinal exploration exposed the pericardial defect, over which a CorMatrix patch was placed. The fistula was then stented endoscopically with endosuture fixation. Poststent esophagram did not show barium leak, and the patient was discharged home. One week later, the patient returned with enterococcal and candida bacteremia and an acute right parietal/occipital lobe infarct. Barium esophagram showed contrast extravasation into the pericardium. The patient rapidly succumbed to his illness and died. Autopsy revealed pericardial abscess posterior to the LA in communication with the esophagus. Extension to the LA was not seen. CONCLUSION: While the surgical treatment of AEF is relatively well established, there is no consensus in the management of PEF. While prior small series have suggested PEF may be managed with esophageal stenting, our case illustrates the limitations of this approach.

Intratumoral injection of the seasonal flu shot converts immunologically cold tumors to hot and serves as an immunotherapy for cancer.

Reprogramming the tumor microenvironment to increase immune-mediated responses is currently of intense interest. Patients with immune-infiltrated "hot" tumors demonstrate higher treatment response rates and improved survival. However, only the minority of tumors are hot, and a limited proportion of patients benefit from immunotherapies. Innovative approaches that make tumors hot can have immediate impact particularly if they repurpose drugs with additional cancer-unrelated benefits. The seasonal influenza vaccine is recommended for all persons over 6 mo without prohibitive contraindications, including most cancer patients. Here, we report that unadjuvanted seasonal influenza vaccination via intratumoral, but not intramuscular, injection converts "cold" tumors to hot, generates systemic CD8+ T cell-mediated antitumor immunity, and sensitizes resistant tumors to checkpoint blockade. Importantly, intratumoral vaccination also provides protection against subsequent active influenza virus lung infection. Surprisingly, a squalene-based adjuvanted vaccine maintains intratumoral regulatory B cells and fails to improve antitumor responses, even while protecting against active influenza virus lung infection. Adjuvant removal, B cell depletion, or IL-10 blockade recovers its antitumor effectiveness. Our findings propose that antipathogen vaccines may be utilized for both infection prevention and repurposing as a cancer immunotherapy.

Paravertebral Nerve Block With Liposomal Bupivacaine for Pain Control Following Video-Assisted Thoracoscopic Surgery and Thoracotomy.

BACKGROUND: Some surgeons have adopted the use of video-assisted thoracoscopic surgery (VATS) or robotic surgery to perform resections for lung cancer. VATS is associated with less pain and a decrease in pulmonary complications compared with open thoracotomies. Long-acting liposomal bupivacaine (LB) intercostal nerve blocks are reported to provide superior pain relief compared with epidural catheters in the first 3 d after a thoracotomy. This study examined whether LB improves pain after VATS and if it provides effective analgesia after a thoracotomy. MATERIALS AND METHODS: A retrospective review was performed on 151 consecutive patients undergoing a VATS or thoracotomy who received paravertebral nerve blocks. VATS patients received paravertebral nerve blocks with LB (VATS-LB) or 0.25% bupivacaine with epinephrine (BE; VATS-BE). Thoracotomy patients received paravertebral nerve blocks via LB injections. Pain scores, narcotic utilization, complications, and hospital length of stay were examined. RESULTS: Fifty patients underwent a VATS-LB, 53 underwent a VATS-BE, and 32 underwent a thoracotomy. Thoracotomy and VATS-LB patients had pain scores lower than VATS-BE patients in the first 48 h after surgery (P < 0.004). Opioid use was not significantly different between the thoracotomy and VATS-LB patients throughout the first 2 wk postoperatively. CONCLUSIONS: LB paravertebral blocks significantly improve postoperative pain in comparison with 0.25% BE blocks in VATS patients. LB paravertebral blocks also provide effective analgesia in patients undergoing thoracotomies.

Synchronous Oligometastatic Non-small Cell Lung Cancer Managed With Curative-Intent Chemoradiation Therapy: Long-term Outcomes From a Single Institution.

PURPOSE: We examined long-term clinical outcomes among patients with synchronous oligometastatic non-small cell lung cancer (NSCLC) treated at our institution with definitive thoracic chemoradiation therapy (CRT) and local therapy to all oligometastatic lesions. METHODS AND MATERIALS: A retrospective review identified 38 patients with synchronous oligometastatic NSCLC (≤3 metastatic lesions) who were treated with definitive CRT to the primary tumor and regional lymph nodes between 1999 and 2017 at our institution. Of the 38 patients, 27 patients (71%) received induction chemotherapy, all of whom responded or stabilized with initial systemic therapy before consideration of CRT. Most patients received chemotherapy concurrently with radiation therapy (n = 32; 84%) and local therapy to the metastatic disease site(s) (n = 34; 89%). We assessed patterns of progression or failure, overall survival (OS), progression-free survival (PFS), and toxicities. RESULTS: The median follow-up duration was 54.9 months. Most patients (84%) presented with N2 to N3 disease. The brain or central nervous system was the most common site of disease progression and occurred in 16 of 28 patients (57%) experiencing any progression and 10 of 16 patients (63%) who initially presented with brain oligometastases. Median OS was 21.1 months (95% confidence interval [CI], 15.6-49.0 months), and median PFS 9.7 months (95% CI, 8.2-14.4 months). The 1-, 2-, and 4-year OS rates were 75.7%, 45.0%, and 33.7%, respectively. On multivariate analysis, both locoregional progression (hazard ratio: 5.8; 95% CI, 2.2-15.0; P = .0003) and distant progression (hazard ratio: 6.0; 95% CI, 2.3-15.4; P = .0002), when treated as time-dependent covariates, were associated with inferior OS. Grade ≥3 esophagitis occurred in 9% and grade ≥3 pneumonitis in 5% of patients with evaluable data. CONCLUSIONS: Patients with synchronous oligometastatic NSCLC and a high regional nodal burden treated with definitive thoracic CRT experienced favorable survival outcomes and low toxicity. At our institution, treating oligometastatic disease with CRT after systemic therapy is incorporated into the treatment plan from the onset of therapy, and we monitor the neuraxis closely for progression during and after treatment. Future research should focus on novel treatment combinations, such as immunotherapy or targeted systemic therapy as appropriate to further improve tumor control and survival.

Vertebral body irradiation during chemoradiation therapy for esophageal cancer contributes to acute bone marrow toxicity.

BACKGROUND: Hematologic toxicity (HT) commonly occurs during chemoradiation therapy (CRT) for esophageal cancer. We sought to determine radiation doses that correlate with declines in blood counts due to vertebral body (VB) irradiation during CRT. METHODS: We analyzed 53 esophageal cancer patients who were treated with weekly neoadjuvant carboplatin, paclitaxel and RT with weekly complete blood counts (CBC) available during treatment. HTs were graded according to the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). Dose volume histogram (DVH) parameters of Vx, defined as percentage of entire bony vertebra (body, pedicles, laminae, processes) receiving at least x Gy of radiation, were collected for VB V5 (VBV5), VBV10-VBV60 in increments of 10, and mean vertebral dose (MVD). Linear and logistic regressions were performed to identify associations between leukopenia nadirs and DVH parameters. Receiver operator curves identified thresholds to avoid grade ≥3 leukopenia. RESULTS: A proportion of 32.1% of patients (n=17) developed grade 3 leukopenia and 5.7% (n=3) developed grade 4 leukopenia. VBV5, VBV10, VBV20, VBV30, and MVD were significantly associated with worsening leukopenia on univariate and multivariate analysis. Associations with leukopenia were not seen with VBV40 and VBV50 DVH values. Thresholds to avoid grade ≥3 leukopenia were VBV10 <49.1%, VBV20 <45.6%, and MVD <17.2 Gy. CONCLUSIONS: VBV5, VBV10, VBV20, VBV30 associate with leukopenia during CRT for esophageal cancer patients. Improved radiation sparing of the VB may decrease HT and may improve tolerability of concurrent chemotherapy and allow for intensification of systemic therapy during RT.

Double-Humanized Mouse Model to Study Bone Morphogenetic Protein (BMP) Signaling in Tumor Xenografts.

The activation of the bone morphogenic protein (BMP) signaling pathway in cancer cells has been shown to enhance migration and tumor angiogenesis and promote survival. The BMP signaling pathway regulates benign cells in the tumor microenvironment and is a known regulator of immune cells. The development of BMP receptor inhibitors has allowed the study of tumor xenografts in mice. We describe a double-humanized mouse model with adoptively transferred human immune and human tumor cells that can be used to assess the effects of BMP inhibitors on these human cells in vivo.

Variations in Initiation Dates of Chemotherapy and Radiation Therapy for Definitive Management of Inoperable Non-Small Cell Lung Cancer Are Associated With Decreases in Overall Survival.

BACKGROUND: We evaluated trends in administration of concurrent chemoradiation therapy (CRT) and how variations in start dates of chemotherapy and radiotherapy affected overall survival (OS) in patients with non-small cell lung cancer (NSCLC) undergoing a course of definitive CRT. MATERIALS AND METHODS: Cases of NSCLC treated with definitive CRT were obtained from the National Cancer Database. A survival analysis was performed with Kaplan-Meier curves and Cox proportional hazards models. Propensity score matching was conducted. RESULTS: On a national level, only 48.6% of patients began concurrent CRT on the same day. In a propensity-matched population, starting CRT within 6 days was associated with improved OS (17.9 months) compared with starting 7 to 13 days apart (16.5 months; P = .04). Starting dual therapy within 6 days of each other was associated with a 7% reduction in the risk of death (hazard ratio, 0.93; P = .05). Furthermore, in a propensity-matched cohort, starting CRT within 3 days was associated with longer survival (18.7 months) compared with 4 to 6 days apart (17.5 months; P = .02). Starting treatment 4 to 6 days apart was associated with an 8% increased risk of death (hazard ratio, 1.08; P = .04). CONCLUSION: A large proportion (48.6%) of patients with unresectable NSCLC do not initiate CRT on the same day as is considered standard by national guidelines. In this population, nonsimultaneous initiation of CRT was associated with differences in OS. Further efforts to understand the mitigating factors and barriers that interfere with timely delivery of concurrent CRT are needed.

Novel bone morphogenetic protein receptor inhibitor JL5 suppresses tumor cell survival signaling and induces regression of human lung cancer.

BMP receptor inhibitors induce death of cancer cells through the downregulation of antiapoptotic proteins XIAP, pTAK1, and Id1-Id3. However, the current most potent BMP receptor inhibitor, DMH2, does not downregulate BMP signaling in vivo because of metabolic instability and poor pharmacokinetics. Here we identified the site of metabolic instability of DMH2 and designed a novel BMP receptor inhibitor, JL5. We show that JL5 has a greater volume of distribution and suppresses the expression of Id1 and pTak1 in tumor xenografts. Moreover, we demonstrate JL5-induced tumor cell death and tumor regression in xenograft mouse models without immune cells and humanized with adoptively transferred human immune cells. In humanized mice, JL5 additionally induces the infiltration of immune cells within the tumor microenvironment. Our studies show that the BMP signaling pathway is targetable in vivo and BMP receptor inhibitors can be developed as a therapeutic to treat cancer patients.

Modern radiotherapy using image guidance for unresectable non-small cell lung cancer can improve outcomes in patients treated with chemoradiation therapy.

BACKGROUND: To investigate the impact of advances in image-guided radiotherapy (IGRT) on the outcomes of patients with non-small cell lung cancer (NSCLC) treated with chemoradiation therapy (CRT). METHODS: We retrospectively reviewed 91 patients with NSCLC treated with definitive CRT using image guidance with daily orthogonal kilovoltage (kV) imaging compared to standard weekly megavoltage (MV) portal verifications. Kaplan-Meier curves for overall survival and locoregional failure were computed and stratified by image guidance techniques. Log-rank tests were used to compare strata. Cox Proportional Hazards models were used to identify risk factors for worse mortality and locoregional control. RESULTS: Fifty-four percent (n=49) of patients received weekly MV portal imaging, while 46% (n=42) underwent IGRT using daily orthogonal kV imaging. kV IGRT was associated with longer median survival (36.4 months) compared to MV imaging (14.9 months; P=0.01). kV imaging was also marginally associated with lower risk of locoregional failure. Median time to local progression in patients imaged with kV was 21.4 months compared to 10.9 months (P=0.065) for those treated with MV portal imaging. CONCLUSIONS: Daily kV imaging appears to be marginally associated with better survival and disease control when compared to MV imaging. Given the small study size and the numerable factors tested, these finding require additional confirmation.

Modern induction chemotherapy before chemoradiation for bulky locally-advanced nonsmall cell lung cancer improves survival.

BACKGROUND: We seek to investigate whether carboplatin-based induction chemotherapy before modern day concurrent chemoradiotherapy (CCRT) improves survival in patients with bulky, locally advanced nonsmall cell lung cancer (NSCLC). MATERIALS AND METHODS: This analysis included 105 patients with Stage II and III NSCLC treated with definitive CCRT from 2003 to 2013. All patients underwent definitive treatment with weekly platinum-based doublet chemotherapy delivered concurrently with 60-66 Gy of thoracic radiotherapy. Thirty patients who received induction chemotherapy before CCRT had T4 disease, N3 disease, or gross tumor volume (GTV) of >150 cm 3. These patients were compared to those with unresectable disease who received CCRT alone without induction chemotherapy. Statistical analysis included univariate and multivariate methods. RESULTS: Mean follow-up time was 15.6 months. Patients treated with carboplatin based induction chemotherapy demonstrated prolonged overall survival (28.2 vs. 14.2 months, P = 0.04), progression free survival (12.6 vs. 9.0 months, P = 0.02), and distant metastasis free survival (15.8 vs. 10.1months, P = 0.05) compared to those who received CCRT alone without induction chemotherapy. Univariate analysis revealed older age, larger GTV, and squamous pathology as negative prognostic factors. When controlling for these factors, Cox regression analysis indicated a trend toward significantly improved overall survival in the induction cohort (P = 0.10). CONCLUSION: In patients with large tumors or bulky nodal NSCLC, carboplatin-based induction chemotherapy may be an important addition to definitive CCRT in the modern era. Our findings strongly support further investigation induction chemotherapy in this population.

Inhibition of BMP and of TGFß receptors downregulates expression of XIAP and TAK1 leading to lung cancer cell death.

BACKGROUND: Bone morphogenetic proteins (BMP) are embryonic proteins that are part of the transforming growth factor (TGFß) superfamily, which are aberrantly expressed in many carcinomas. Inhibition of BMP receptors with small molecule inhibitors decreases growth and induces death of lung cancer cells, which involves the downregulation of Id1 and Id3 by a Smad dependent mechanism. Developmentally, BMP and TGFß signaling utilizes Smad-1/5 independent mechanisms to stabilize the expression of X-linked inhibitor of apoptosis protein (XIAP) and activate TGFß activated kinase 1 (TAK1), which are known to be potent inhibitors of apoptosis. The role of BMP signaling in regulating XIAP and TAK1 in cancer cells is poorly understood. Furthermore, the interaction between the BMP and TGFß signaling cascades in regulating the activation of TAK1 in cancer cells has not been elucidated. METHODS: Feedback regulation between the BMP and TGFß signaling pathways and their regulation of XIAP, TAK1, and Id1 were examined in lung cancer cells utilizing siRNA and inhibitors targeting BMP type I receptors, inhibitors of BMP and TGFß type I receptors, and an inhibitor of BMP and TGFß type I and type II receptors. RESULTS: We show that upon inhibition of BMP signaling in lung cancer cells, the TGFß signaling cascade is activated. Both the BMP and TGFß pathways activate TAK1, which then increases the expression of Id1. Inhibition of TGFß signaling increased Id1 expression except when BMP signaling is suppressed, which then causes a dose-related decrease in the expression of Id1. Inhibition of both BMP and TGFß signaling enhances the downregulation of TAK1. Our data also suggests that the blockade of the BMP type II receptor enhances the downregulation XIAP, which is important in decreasing the activity of TAK1. Knockdown studies demonstrate that both XIAP and TAK1 regulate the survival of lung cancer cells. CONCLUSIONS: This paper highlights that targeting the BMP and TGFß type I and type II receptors causes a downregulation of XIAP, TAK1, and Id1 leading to cell death of lung cancer cells. Small molecule inhibitors targeting the BMP and TGFß receptors represents a potential novel means to treat cancer patients.