Colorectal Lung Metastases Research Articles

Adjuvant chemotherapy for isolated resectable colorectal lung metastasis: A retrospective study using inverse probability treatment weighting propensity analysis.

The benefit of adjuvant chemotherapy (ACT) for patients with no evidence of disease after pulmonary metastasis resection (PM) from colorectal cancer (CRC) remains controversial. To assess the efficacy of ACT in patients after PM resection for CRC. This study included 96 patients who underwent pulmonary metastasectomy for CRC at a single institution between April 2008 and July 2023. The primary endpoint was overall survival (OS); secondary endpoints included cancer-specific survival (CSS) and disease-free survival (DFS). An inverse probability of treatment-weighting (IPTW) analysis was conducted to address indication bias. Survival outcomes compared using Kaplan-Meier curves, log-rank test, Cox regression and confirmed by propensity score-matching (PSM). With a median follow-up of 27.5 months (range, 18.3-50.4 months), the 5-year OS, CSS and DFS were 72.0%, 74.4% and 51.3%, respectively. ACT had no significant effect on OS after PM resection from CRC [original cohort: P = 0.08; IPTW: P = 0.15]. No differences were observed for CSS (P = 0.12) and DFS (P = 0.68) between the ACT and non-ACT groups. Multivariate analysis showed no association of ACT with better survival, while sublobar resection (HR = 0.45; 95%CI: 0.20-1.00, P = 0.049) and longer disease-free interval (HR = 0.45; 95%CI: 0.20-0.98, P = 0.044) were associated with improved survival. ACT does not improve survival after PM resection for CRC. Further well-designed randomized controlled trials are needed to determine the optimal ACT regimen and duration.

Treatment of Colorectal Lung Metastases: Two Centers Retrospective Study

Introduction: Clear guidelines for colorectal lung metastasis (LM) treatment are not available. This study aimed to provide insight into the treatment strategies and efficacy of local and systemic therapy in patients with LM eligible for (potentially) curative treatment. Methods: This was a retrospective study of patients with ≤5 LM discussed in two tertiary referral centers. Patient and tumor characteristics were compared between treatment groups. Treatment strategies were compared between centers and survival data between treatment groups, local treatment modalities, and treating centers. Results: Ninety-two patients (median 2 LMs) were included. Seventy-one (77%) patients underwent local treatment (17 surgery, 13 ablation, 38 radiotherapy, 3 combination of local treatments) and 21 (23%) with systemic therapy alone. The latter group more frequently had extrapulmonary metastases (81.0% vs. 26.8%, p < 0.001) and synchronous presentation of LM (23.8% vs. 7.0%, p = 0.045). Choice of local versus systemic therapy and time to start treatment after diagnosis (median 109 days, IQR 44–240 vs. 88 days, IQR 53–168) were comparable between centers. Three-year survival rates did not differ between treatment groups, local treatment modalities, or treating centers. Conclusion: Treatment strategies and oncological outcomes were rather similar between centers. Survival outcomes were not different between locally and systemically treated patients.

Survival outcome following surgical versus non-surgical treatment of colorectal lung metastasis—a retrospective cohort study

PurposeThe optimal management of colorectal lung metastases (CRLM) is still controversial. The aim of this study was to compare surgical and non-surgical treatment for CRLM regarding the prognostic outcome.MethodsThis retrospective single-center cohort study included 418 patients, who were treated from January 2000 to December 2018 at a German University Hospital due to their colorectal carcinoma and had synchronous or metachronous lung metastases. Patients were stratified according the treatment of the CRLM into two groups: surgical resection of CRLM versus no surgical resection of CRLM. The survival from the time of diagnosis of lung metastasis was compared between the groups.ResultsTwo- and 5-year overall survival (OS) from the time of diagnosis of lung metastasis was 78.2% and 54.6%, respectively, in our cohort. Patients undergoing pulmonary metastasectomy showed a significantly better 2- and 5-year survival compared to patients with non-surgical treatment (2-year OS: 98.1% vs. 67.9%; 5-year OS: 81.2% vs. 28.8%; p < 0.001). Multivariate Cox regression revealed the surgical treatment (HR 4.51 (95% CI = 2.33–8.75, p < 0.001) and the absence of other metastases (HR 1.79 (95% CI = 1.05–3.04), p = 0.032) as independent prognostic factors in patients with CRLM.ConclusionOur data suggest that patients with CRLM, who qualify for surgery, benefit from surgical treatment. Randomized controlled trials are needed to confirm our findings.Clinical trial registry numberThe work has been retrospectively registrated at the German Clinical Trial Registry (DRKS00032938).

Intraoperative molecular imaging of colorectal lung metastases with SGM-101: a feasibility study

PurposeMetastasectomy is a common treatment option for patients with colorectal lung metastases (CLM). Challenges exist with margin assessment and identification of small nodules, especially during minimally invasive surgery. Intraoperative fluorescence imaging has the potential to overcome these challenges. The aim of this study was to assess feasibility of targeting CLM with the carcinoembryonic antigen (CEA) specific fluorescent tracer SGM-101.MethodsThis was a prospective, open-label feasibility study. The primary outcome was the number of CLM that showed a true positive fluorescence signal with SGM-101. Fluorescence positive signal was defined as a signal-to-background ratio (SBR) ≥ 1.5. A secondary endpoint was the CEA expression in the colorectal lung metastases, assessed with the immunohistochemistry, and scored by the total immunostaining score.ResultsThirteen patients were included in this study. Positive fluorescence signal with in vivo, back table, and closed-field bread loaf imaging was observed in 31%, 45%, and 94% of the tumors respectively. Median SBRs for the three imaging modalities were 1.00 (IQR: 1.00–1.53), 1.45 (IQR: 1.00–1.89), and 4.81 (IQR: 2.70–7.41). All tumor lesions had a maximum total immunostaining score for CEA expression of 12/12.ConclusionThis study demonstrated the potential of fluorescence imaging of CLM with SGM-101. CEA expression was observed in all tumors, and closed-field imaging showed excellent CEA specific targeting of the tracer to the tumor nodules. The full potential of SGM-101 for in vivo detection of the tracer can be achieved with improved minimal invasive imaging systems and optimal patient selection.Trial registrationThe study was registered in ClinicalTrial.gov under identifier NCT04737213 at February 2021.

Optimal timing for lung metastasectomy in patients with colorectal cancer.

OBJECTIVESThe possibility of occult metastasis remains a concern when deciding on lung metastasectomy. This study aimed to evaluate the utility of our two-step determination, which required confirmation that no new metastases had occurred over 3 months before surgery.METHODSPatients who were referred for colorectal lung metastases between 2007 and 2015 were reviewed. Immediate wedge resection was performed for cases with a single peripheral metastasis, whereas surgical indications for others were determined by the two-step determination. Early increase was defined as the emergence of new metastases within 4 months after the diagnosis of lung metastases.RESULTSAmong 369 patients included, 92 were unresectable upon initial diagnosis, and 74 with single peripheral metastasis underwent immediate wedge resection. Surgical indications for the remaining 203 patients were ascertained based on the two-step determination. Surgery was not indicated in 48 patients (24%) due to new metastases or a favourable response to chemotherapy, with a median waiting duration of 4.8 months. Those who did not receive surgery had a worse prognosis than those who did (5-year overall survival: 21% vs 69%, P < 0.001) and were comparable to the initially unresectable group (5-year overall survival: 23%). Thirty-eight patients with early increase had lower surgical resection rates and worse prognoses than those without. Multivariable analysis identified early increase as an independent prognostic factor (hazard ratio: 4.49, P < 0.001).CONCLUSIONSPatients with colorectal lung metastasis who developed new metastasis during the waiting period exhibited poor prognosis, suggesting the utility of the two-step determination of surgical indications.

High Yield of Chest X-ray in the Follow-Up of Colorectal Cancer

Purpose: Worldwide, colorectal carcinoma (CRC) has a high incidence and a substantial cancer-related mortality. The recurrence risk is 30–50% and lung metastases are common. Treatment of lung metastases with stereotactic ablative radiotherapy (SABR) or metastasectomy may increase survival. The best modality for thoracic screening in the follow-up, however, remains controversial. In this study, we aimed to unravel the additional value of routine chest X-ray (CXR) for detecting lung metastases during the follow-up of CRC patients treated with curative surgery. Methods: Between 2013 and 2017, 668 CRC patients were treated with curative intent, of whom 633 patients were included in follow-up, which consisted of CXR, serum Carcino-Embryonic Antigen (CEA) and ultrasound of the liver. Patients who developed lung metastases, diagnosed with CXR and characterised by a normal concomitant serum CEA level, were identified. Number, size and treatment of lung metastases were described. Results: Thirty-four (5.4%) patients developed lung metastases. Seventeen (50%) were detected by CXR without pathological CEA levels. Eleven (65%) of these patients were treated with curative intent, whereas 21% of patients with lung metastases and elevated CEA levels were treated with curative intent (p = 0.049). Higher numbers of lung metastases were associated with a lower chance of curative treatment. Conclusions: More than 50% of patients with lung metastases on CXR in the follow-up would not have been detected with CEA-triggered imaging only. In addition, patients with colorectal lung metastases without elevated CEA levels were often suitable for curative treatment and, therefore, CXR seems to have additional value within the follow-up of CRC.

Histological growth patterns and molecular analysis of resected colorectal lung metastases

Lung is the site of metastasis in about 15–25 % of colorectal cancer (CRC) patients. Lung metastasectomy of CRC represents a standard therapy in patients with resectable metastases. In this study we investigated both histological patterns of metastases and mutations in MAPkinase pathway genes and their relationship to prognosis. The study included 74 patients that underwent metastasectomy of colorectal lung metastasis (CLM). In patients that underwent surgical resection of more than one metastasis in the same operation the largest was chosen. In patients that had undergone multiple lung metastasectomy only the sample from the first metastasectomy was included. Histologically metastases were scored according to amount and distribution of necrosis and fibrosis and three patterns were identified: “pattern A”, metastasis with extensive, confluent central necrosis surrounded by a rim of neoplastic glands; “pattern B”, metastasis characterized by a proliferation of neoplastic glands in a dense stroma with focal necrosis mainly intraglandular; “pattern C”, metastasis with a mixed A and B morphology. In all samples direct sequencing of exon 2 of KRAS and NRAS genes and exon 15 of BRAF genes was carried out.Histological patterns weren’t related to metastasis size or other clinical features however pattern C metastases showed a significant worst disease free survival (DFS). KRAS mutations were observed in 39 % of patients. Mutations in KRAS codon 13 resulted significantly associated with synchronous metastasis and poor prognosis. No mutations were identified in exon 2 NRAS gene whilst 1.4 % harboured a mutation in BRAF. To our knowledge this is the first study that investigates in a large series of CLM histological growth patterns, molecular alterations and their relationship to prognosis. Our data suggest a prognostic role in CLM of KRAS specific mutations and histopathological patterns.

Subpleural Lymphatic Permeation in Colorectal Lung Metastases

A 71-year-old woman with a history of rectal cancer 2 years earlier was referred to our department to manage bilateral pulmonary nodules. A chest computed tomography scan showed one lung nodule in the right S1 (13 mm) segment and two nodules in the left S9 (30 mm) and left S10 (10 mm) segments. After resection of the right tumor, a wedge resection was scheduled for the left tumors. However, rosarylike structures were noted beneath the visceral pleura to the hilum (Figures 1A-1C, arrows). We suspected lymphatic invasion; hence, partial resection was considered inappropriate for R0 resection.

Meta-Analysis of Survival Following Pulmonary Resection for Colorectal Cancer Metastases

Background: Controversy exists regarding the optimal management of colorectal lung metastases (CRLM). This meta-analysis compared surgical (Surg) vs interventional (Chemotherapy and/or Radiotherapy) and observational non-surgical (NSurg) management of CRLM. Methods: A systematic review of the major databases including Medline, Embase, SCOPUS, and the Cochrane library was performed. Results: Ten studies including 2232 patients; 1551 (69%) comprised the Surg cohort, 521 (23%) the interventional NSurg group and 160 (7%), the observational NSurg group. A significantly higher overall survival was observed when Surg was compared to interventional NSurg at one-year (Surg 89%, 359/402 interventional NSurg 70%, 343/625, OR 2.76 (CI 2.10-3.63), P< 0.001), at three-years (Surg 59%, 857/1444 interventional NSurg 26%, 138/521, OR 2.61 (CI 1.65-4.15), P=0.002), at-five years (Surg 47%, 533/1144 interventional NSurg 23%, 45/196, OR 3.24 (CI 1.42-7.39), P=0.009) and at ten-years (Surg 27%, 306/1122 interventional NSurg 1%, 2/168, OR 15.64 (CI 1.87-130.76), P=0.031). In contrast however, Surg was associated with a greater overall survival than observational NSurg at only one-year (Surg 89%, 1009/1132 observational NSurg 67%, 93/138, OR 4.49 (CI 1.16-17.40), P=0.041) and was similar to observational NSurg at all other overall survival time points. Comparable survival was observed among Surg and overall NSurg cohorts at three- and five-year survival in articles published within the last three years. Conclusions: Recent evidence suggests comparable survival with Surg and NSurg modalities for CRLM, contrasting to early evidence where Surg had an improved survival. Significant selection bias.

Inhibitory Effect of Gallotannin on Lung Metastasis of Metastatic Colorectal Cancer Cells by Inducing Apoptosis, Cell Cycle Arrest and Autophagy.

Colorectal cancer (CRC) is the second most common cause of cancer death in the world, and metastatic CRC is a major cause of cancer death. Gallotannin (GT), a polyphenolic compound, has shown various biological effects such as anti-oxidant, anti-inflammatory, antimicrobial, and antitumor effects. However, the effects of GT on metastatic CRC cells are not completely understood. This study aimed to investigate the anti-metastatic effect of GT and the underlying mechanisms on metastatic CRC cells. Oral administration of GT suppressed the lung metastasis of metastatic CRC cells in the experimental mouse model. GT decreased the viability of metastatic CRC cell lines, including CT26, HCT116, and SW620, by inducing apoptosis through the activation of extrinsic and intrinsic pathways, cell cycle arrest through inactivation of CDK2/cyclin A complex, and autophagic cell death through up-regulation of LC3B and p62 levels. GT regulated PI3K/AKT/mTOR and AMPK signaling pathways, which are critical for the development and maintenance of cancer. Additionally, non-cytotoxic concentrations of GT can suppress migration and invasion of CRC cells by inhibiting the expression and activity of matrix metalloproteinase (MMP)-2 and MMP-9 and epithelial-mesenchymal transition by downregulating the expression of mesenchymal markers including snail, twist, and vimentin. In conclusion, GT prevented colorectal lung metastasis by reducing survival and inhibiting the metastatic phenotypes of CRC cells.

Meta-analysis of survival outcomes following surgical and non surgical treatments for colorectal cancer metastasis to the lung.

Controversy exists regarding the optimal management of colorectal lung metastases (CRLM). This meta-analysis compared surgical (Surg) versus interventional (chemotherapy and/or radiotherapy) and observational non-surgical (NSurg) management of CRLM. A systematic review of the major databases including Medline, Embase, SCOPUS and the Cochrane library was performed. One randomized and nine observational studies including 2232 patients: 1551 (69%) comprised the Surg cohort, 521 (23%) the interventional NSurg group and 160 (7%) the observational NSurg group. A significantly higher overall survival (OS) was observed when Surg was compared to interventional NSurg at 1 year (Surg 88%, 310/352; interventional NSurg 64%, 245/383; odds ratio (OR) 2.77 (confidence interval (CI) 1.94-3.97), P = 0.001), at 3 years (Surg 59%, 857/1444; interventional NSurg 26%, 138/521; OR 2.61 (CI 1.65-4.15), P = 0.002), at 5 years (Surg 47%, 533/1144; interventional NSurg 23%, 45/196; OR 3.24 (CI 1.42-7.39), P = 0.009) and at 10 years (Surg 27%, 306/1122; interventional NSurg 1%, 2/168; OR 15.64 (CI 1.87-130.76), P = 0.031). Surg was associated with a greater OS than observational NSurg at only 1 year (Surg 92%, 98/107; observational NSurg 83%, 133/160; OR 6.69 (CI 1.33-33.58), P = 0.037) and was similar to observational NSurg at all other OS time points. Comparable survival was observed among Surg and overall NSurg cohorts at 3- and 5-year survival in articles published within the last 3 years. Recent evidence suggests comparable survival with Surg and NSurg modalities for CRLM, contrasting to early evidence where Surg had an improved survival. Significant selection bias contributes to this finding, prompting the need for high powered randomized controlled trials and registry data.

Long-Term Outcomes in Percutaneous Radiofrequency Ablation for Histologically Proven Colorectal Lung Metastasis

IntroductionTo evaluate the long-term outcome of image-guided radiofrequency ablation (RFA) when treating histologically confirmed colorectal lung metastasis in terms of overall survival (OS), progression-free survival (PFS) and local tumour control (LTC).Materials and MethodsRetrospective single-centre study. Consecutive RFA treatments of histologically proven lung colorectal metastases between 01/01/2008 and 31/12/14. The primary outcome was patient survival (OS and PFS). Secondary outcomes were local tumour progression (LTP) and complications. Prognostic factors associated with OS/ PFS were determined by univariate and multivariate analyses.ResultsSixty patients (39 males: 21 females; median age 69 years) and 125 colorectal lung metastases were treated. Eighty percent (n = 48) also underwent lung surgery for lung metastases. Mean metastasis size (cm) was 1.4 ± 0.6 (range 0.3–4.0). Median number of RFA sessions was 1 (1–4). During follow-up (median 45.5 months), 45 patients died (75%). The estimated OS and PFS survival rates at 1, 3, 5, 7, 9 years were 96.7%, 74.7%, 44.1%, 27.5%, 16.3% (median OS, 52 months) and 66.7%, 31.2%, 25.9%, 21.2% and 5.9% (median PFS, 19 months). The LTC rate was 90% with 6 patients developing LTP with 1-, 2-, 3- and 4-year LTP rates of 3.3%, 8.3%, 10.0% and 10.0%. Progression-free interval < 1 year (P = 0.002, HR = 0.375) and total number of pulmonary metastases (≥ 3) treated (P = 0.037, HR = 0.480) were independent negative prognostic factors. Thirty-day mortality rate was 0% with no intra-procedural deaths.ConclusionThe long-term OS and PFS following RFA for the treatment of histologically confirmed colorectal lung metastases demonstrate comparable oncological durability to surgery.

Galla�Rhois water extract inhibits lung metastasis by inducing AMPK‑mediated apoptosis and suppressing metastatic properties of colorectal cancer cells

Galla Rhois is a commonly used medicine in East Asia for the treatment of several diseases. However, the effects of Galla Rhois on the metastasis of colorectal cancer (CRC) and the underlying molecular mechanisms have not been studied. We investigated the anti-metastatic properties of Galla Rhois water extract (GRWE) on metastatic CRC cells. The effect of GRWE on the viability of colon 26 (CT26) cells was evaluated using WST-8 assay. Annexin V assay and western blot analysis were performed to elucidate the underlying molecular mechanisms involved in apoptosis. GRWE suppressed viability of CT26 cells by inducing apoptosis through the cleavage of caspase-3 and PARP, downregulation of caspase-8, caspase-9, Bcl-2 and Bcl-xL, and upregulation of Bax. Metastatic phenotypes such as epithelial-mesenchymal transition (EMT), migration, and invasion of CRC cells were investigated by real-time reverse transcription polymerase chain reaction, wound healing assay, and matrigel invasion assay, respectively. Non-cytotoxic concentrations of GRWE inhibited EMT in CRC cells by regulating the expression of EMT markers. GRWE attenuated cell migration and invasion through the inhibition of matrix metalloproteinase (MMP)-2 and MMP-9 activity. Moreover, GRWE suppressed colorectal lung metastasis in vivo, suggestive of its potential application for the treatment of colorectal metastasis.

Gomisin A Suppresses Colorectal Lung Metastasis by Inducing AMPK/p38-Mediated Apoptosis and Decreasing Metastatic Abilities of Colorectal Cancer Cells.

Gomisin A (G.A) is a dietary lignan compound from Schisandra chinensis. In this study, the effect of G.A on the proliferation and metastasis of colorectal cancer (CRC) cells was investigated using several CRC cell lines and a lung metastasis mouse model. Both oral and intraperitoneal administration of G.A (50 mg/kg) inhibited lung metastasis of CT26 cells. Various concentrations of G.A were incubated with CRC cell lines and their viability was determined using a cell counting kit-8 assay. G.A significantly decreased the viability of various CRC cell lines, whereas it did not change the proliferation of normal colon cells. G.A induced G0/G1 phase arrest and apoptosis of CT26 and HT29 cells by regulating cyclin D1/cyclin-dependent kinase 4 (CDK4) expression and apoptotic proteins such as caspases and B-cell lymphoma-2 (Bcl-2) family proteins, respectively. G.A-induced apoptosis was mediated by AMPK/p38 activation in CRC cells. A non-cytotoxic concentration of G.A inhibited epithelial–mesenchymal transition of CRC cells by modulating E-cadherin and N-cadherin expression levels. Moreover, the migration and invasion of CRC cells were reduced by G.A treatment. Especially, G.A decreased matrix metalloproteinase (MMP)-2 and MMP-9 expressions and activities. G.A ameliorated lung metastasis of CRC cells by decreasing cell survival and metastatic abilities of CRC cells. Thus, G.A might be a potential novel therapeutic agent for metastatic CRC.

203P Combined pulmonary metastasectomy and chemotherapy in patients with colorectal lung metastases and concurrent extrapulmonary disease

203P Combined pulmonary metastasectomy and chemotherapy in patients with colorectal lung metastases and concurrent extrapulmonary disease

Current approaches to treating patients with colorectal lung metastases

Current approaches to treating patients with colorectal lung metastases

A wedge resection in awake surgery for a small PET positive nodule of the lingula in a patient with suspected colorectal lung metastasis

A wedge resection in awake surgery for a small PET positive nodule of the lingula in a patient with suspected colorectal lung metastasis

Effect of Korean Red Ginseng extract on colorectal lung metastasis through inhibiting the epithelial–mesenchymal transition via transforming growth factor-β1/Smad-signaling-mediated Snail/E-cadherin expression

BackgroundIn colorectal cancer (CRC), 40–60% of patients develop metastasis. The epithelial–mesenchymal transition (EMT) is a pivotal and intricate process that increases the metastatic potential of CRC. The aim of this study was to investigate the effect of Korean Red Ginseng extract (RGE) on colorectal metastasis through inhibition of EMT and the metastatic abilities of CRC cells. MethodsTo investigate the effect of RGE on the metastatic phenotypes of CRC cells, CT26 and HT29 cells were evaluated by using an adhesion assay, a wound-healing assay, an invasion assay, zymography, and real-time reverse transcription–polymerase chain reaction. Western-blot analysis was conducted to elucidate the molecular mechanisms of RGE, which showed an inhibitory effect on the transforming growth factor-β1 (TGF-β1)-induced EMT in HT29 cells. Additionally, the antimetastatic effect of RGE was evaluated in a mouse model of lung metastasis injected with CT26 cells. ResultsRGE decreased the adhesion and migration ability of the CT26 cells and TGF-β1-treated HT29 cells. The invasion ability was also reduced by RGE treatment through the inhibition of matrix metalloproteinase-9 expression and activity. Moreover, RGE suppressed the TGF-β1-induced EMT via TGF-β1/Smad-signaling-mediated Snail/E-cadherin expression in HT29 cells and lung tissue in CT26 tumor-bearing mice. ConclusionOur results demonstrated that RGE inhibited colorectal lung metastasis through a reduction in metastatic phenotypes, such as migration, invasion, and the EMT of CRC cells.

Abstract 201: Targeting colorectal cancer lung metastasis microenvironment with PI3K inhibitors and chemotherapy

Abstract Introduction: Colorectal cancer (CRC) is the second leading cause of cancer deaths in the US; systemic metastasis to the lungs occurs in approximately 10-20% of patients with CRC. The toxicity of currently available anticancer drugs and the inefficiency of chemotherapeutic treatments, especially for advanced stages of the CRC metastatic disease, have severely limited the treatment options in patients with CRC lung metastasis. Here, we evaluated nanocarrier that accumulates selectively in normal lung stroma and lung metastasis tumor microenvironment. The purpose of our study was to: (i) demonstrate lung-selective delivery of nanoparticles into the tumor microenvironment and surrounding normal parenchyma as a targeted therapy for CRC lung metastasis, and (ii) evaluate effect of lung selective delivery of PX-866 and SN-38 loaded nanoparticles on CRC lung metastasis growth. Methods: (1) HT29 LungM3 cell line was derived from the human CRC line HT29 following multiple rounds of in vivo selection for lung metastasis in immunodeficient mice. (2) Polymeric nanoparticles were constructed and loaded with fluorescent dye (Alexa 547), pan-PI3K inhibitor PX-866 or SN-38. Fluorescent nanoparticles were administered intravenously into mice at 1, 4, 8, 24h timepoints. (3) Nanoparticle drug delivery was quantified in lung, liver and kidney tissue samples by HPLC. (4) CT26 and HT29 LungM3 cell lines were injected intravenously to establish lung metastasis. Mice were then treated with PX-866 and SN-38 loaded nanoparticles every 3 days intravenously for 31 days. Results: Lung selective accumulation of Alexa-546 fluorescently-labeled nanoparticles was confirmed by confocal imaging of frozen tissue sections from lung, liver, kidney and spleen. Selective PI3K inhibition in lung tissue was confirmed by western blot analysis of protein extracts from lung, liver, kidney and spleen for pAkt (S473) expression. HPLC analysis showed predominant PX-866 drug delivery to lungs and minimal drug delivery to kidney and liver tissues. Treatment with PX-866 loaded nanoparticles demonstrated a marked suppression of lung metastasis growth; CRC lung metastases were not detected after treatment with SN-38 loaded nanoparticles. Notably, administration of PX-866 and SN-38 nanoparticles had no deleterious effect on normal lung, kidney or liver parenchyma. Conclusions: We demonstrate selective and efficient delivery of drug-loaded nanoparticles to lungs with minimal accumulation in kidneys, liver and immune system, suggesting that lung selective drug delivery is a viable treatment strategy for CRC lung metastasis. Moreover, treatment of mice with CRC lung metastases with either PX-866 or SN-38 loaded nanoparticles resulted in a marked suppression of metastatic growth. Polymeric nanocarriers have a potential to revolutionize drug delivery and to significantly improve current approaches to the treatment of patients with CRC lung metastasis. Citation Format: Piotr Rychahou, Younsoo Bae, Derek A. Reichel, Yekaterina Zaytseva, Eun Y. Lee, Heidi L. Weiss, B. Mark Evers. Targeting colorectal cancer lung metastasis microenvironment with PI3K inhibitors and chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 201. doi:10.1158/1538-7445.AM2017-201

β-Lapachone Inhibits Lung Metastasis of Colorectal Cancer by Inducing Apoptosis of CT26 Cells.

Background: β-Lapachone is a quinone-containing compound found in red lapacho (Tabebuia impetiginosa, syn. T avellanedae) trees. Lapacho has been used in traditional medicine by several South and Central American indigenous people to treat various types of cancer. The purpose of this study was to investigate the antimetastatic properties of β-lapachone and the underlying mechanisms using colon cancer cells. Methods: This research used metastatic murine colon cancer cell lines, colon 26 (CT26) and colon 38 (MC38). A WST assay, annexin V assay, cell cycle analysis, wound healing assay, invasion assay, western blot analysis, and real-time reverse transcription–polymerase chain reaction were performed to examine the effects of β-lapachone on metastatic phenotypes and molecular mechanisms. The effect of β-lapachone on lung metastasis was assessed in a mouse experimental metastasis model. Results: We found that the inhibition of proliferation of the colon cancer cell lines by β-lapachone was due to the induction of apoptosis and cell cycle arrest. β-Lapachone induced the apoptosis of CT26 cells through caspase-3, -8, and -9 activation; poly(ADP-ribose) polymerase cleavage; and downregulation of the Bcl-2 family in a dose- and time-dependent manner. In addition, a low concentration of β-lapachone decreased the cell migration and invasion by decreasing the expression of matrix metalloproteinases-2 and -9, and increased the expression of tissue inhibitors of metalloproteinases-1 and -2. Moreover, β-lapachone treatment regulated the expression of epithelial-mesenchymal transition markers such as E- and N-cadherin, vimentin, β-catenin, and Snail in CT26 cells. In the mouse experimental metastasis model, β-lapachone significantly inhibited the lung metastasis of CT26 cells. Conclusions: Our results demonstrated the inhibitory effect of β-lapachone on colorectal lung metastasis. This compound may be useful for developing therapeutic agents to treat metastatic cancer.