We report a case of effective weekly paclitaxel (TXL) administration for metastatic gastric cancer. TXL (80 mg/m2) was infused over 1 hour after short premedication on an outpatient basis. Administration was continued for 3 weeks followed by 1 week rest. A 74-year-old man was diagnosed with recurrence 49 months after surgery for gastric cancer. He was treated with 5-fluorouracil and cisplatin, and thrombocytopenia (grade 3) and creatinin elevation (grade 1) were observed and assessed as progressive disease 2 months after the treatment. We attempted weekly TXL administration and after 5 courses assessed the patient as having a partial response. The treatment is ongoing. The toxic event was leukopenia (grade 2), with no episode of thrombocytopenia. The patient did not complain of nausea or vomiting, and his quality of life was fair during the treatment. Weekly TXL administration is a useful treatment for metastatic gastric cancer.
Current treatments for liver metastases arising from primary breast and lung cancers are minimally effective. One reason for this unfavorable outcome is that liver metastases are poorly vascularized, limiting the ability to deliver therapeutics from the systemic circulation to lesions. Seeking to enhance transport of agents into the tumor microenvironment, we designed a system in which nanoparticle albumin-bound paclitaxel (nAb-PTX) is loaded into a nanoporous solid multistage nanovector (MSV) to enable the passage of the drug through the tumor vessel wall and enhance its interaction with liver macrophages. MSV enablement increased nAb-PTX efficacy and survival in mouse models of breast and lung liver metastasis. MSV-nAb-PTX also augmented the accumulation of paclitaxel and MSV in the liver, specifically in macrophages, whereas paclitaxel levels in the blood were unchanged after administering MSV-nAb-PTX or nAb-PTX. In vitro studies demonstrated that macrophages treated with MSV-nAb-PTX remained viable and were able to internalize, retain, and release significantly higher quantities of paclitaxel compared with treatment with nAb-PTX. The cytotoxic potency of the released paclitaxel was also confirmed in tumor cells cultured with the supernatants of macrophage treated with MSV-nAB-PTX. Collectively, our findings showed how redirecting nAb-PTX to liver macrophages within the tumor microenvironment can elicit a greater therapeutic response in patients with metastatic liver cancer, without increasing systemic side effects.
Developing novel strategies against treatment-resistant triple negative breast cancer (TNBC) cells remains a significant challenge. The ErbB family, including epidermal growth factor receptor (EGFR), plays key roles in metastasis, tumorigenesis, cell proliferation, and drug resistance. Recently, these characteristics have been linked to a small subpopulation of cells classified as cancer stem cells (CSC) which are believed to be responsible for tumor initiation and maintenance. Ixabepilone is a new generation microtubule-stabilizing agent, which has been expected to be more efficacious than conventional taxanes. Here we aim to investigate whether the EGFR monoclonal antibody Cetuximab, in combination with Ixabepilone, is more effective in eliminating CSC populations compared to chemotherapy alone in TNBC. Representative TNBC cell lines (MDA-MB-231 and SUM159) were used to evaluate breast CSC populations. We used fluorescence-activated cell sorter analysis (CD44+ and CD24-/low, or Aldefluor+) and a self-renewal assay called mammosphere formation efficiency (MSFE) to measure CSC population size after treatment with Cetuximab, or Cetuximab plus Ixabepilone in vitro. Although there was no significant decrease in cell viability, Cetuximab reduced MSFE and the CSC population in breast cancer cells in vitro and in vivo through inhibition of autophagy. Also, SUM159 and MDA-MB-231 orthotopic tumors demonstrated partial response to Centuximab or Ixabepilone monotherapy; however, the effect of the combination treatment was significant only in SUM159 tumors (p <0.0001), when compared to Ixabepilone alone. Overall, our findings demonstrate that EGFR-targeted therapy by Cetuximab effectively reduces the CSC population in TNBC tumors. However, combination therapy with Ixabepilone may be effective only in a small subset of TNBCs, warranting further investigation of alternative approaches to target multiple pathways for TNBC treatment.
The restriction enzyme-based digital methylation-specific polymerase chain reaction (RE-dMSP) assay is useful for diagnosing sentinel lymph node (SN) metastasis in patients with breast cancer, by detecting tumor-derived methylated Ras association domain-containing protein 1 (RASSF1A). In addition, this assay has high concordance (95.0%) with one-step nucleic acid amplification (OSNA). The present study aimed to perform RE-dMSP using OSNA lysate from more patients and to re-evaluate its clinical usage. Overall, 418 SNs from 347 patients were evaluated using both OSNA and RE-dMSP. The concordance rate was 83.3% (348/418). RASSF1A methylation of the primary tumors was negative in 36 patients. When these patients were excluded, the concordance rate improved to 88.2% (330/374). Of the 79 OSNA-negative cases, 19 were RE-dMSP-positive, although all were positive for cytokeratin 19 expression in the primary tumor, suggesting that RE-dMSP can detect tumor-derived DNA with a higher sensitivity. The percent of methylated reference of the breast tumors showed a wide variety in the 16 OSNA-positive/RE-dMSP-negative cases, and such variability of methylation could have affected the results in these patients. In conclusion, although RE-dMSP can diagnose SN metastasis with high sensitivity and accuracy, and can be a supplementary tool to OSNA in breast cancer, RE-dMSP showed certain discordance with OSNA and critically depended on the absence or heterogeneity of DNA methylation in breast tumors. Further research is expected to develop an assay targeting other DNA alterations, such as mutations.
Although prognostic markers for early estrogen receptor ( ER )‐positive breast cancer have been extensively developed, predictive markers for adjuvant endocrine therapy are still lacking. Focusing on the mechanisms underlying endocrine resistance, we investigated whether the endocrine sensitivity of ER ‐positive breast cancer cells was correlated with the expression of aspartate‐β‐hydroxylase ( ASPH ), which is involved in the development of hepatocellular carcinoma. ASPH expression in ER ‐positive and tamoxifen‐resistant breast cancer cells was upregulated by the MAPK and phosphoinositide‐3 kinase ( PI 3K) pathways, which both play pivotal roles in endocrine resistance. In the clinical setting, ASPH expression was negatively correlated with recurrence‐free survival of luminal B breast cancer patients that received adjuvant endocrine therapy, but not in patients that did not receive adjuvant endocrine therapy. Luminal B breast cancer is one of the intrinsic molecular subtypes identified by the Prediction Analysis of Microarray 50 ( PAM 50) multiple gene classifier, and because of its poor response to endocrine therapy, chemotherapy in addition to endocrine therapy is generally required after surgical resection. Our results suggest that the endocrine sensitivity of luminal B breast cancer can be assessed by examining ASPH expression, which promotes the consideration of a prospective study on the association between ASPH expression at the mRNA and protein levels in luminal B breast cancer and subsequent response to endocrine therapy.
Abstract This study is aimed to evaluate and enhance the albumin-bound paclitaxel (nab-PTX) in multistage vector (MSV) for liver metastasis treatment using in silico modeling based on in vitro data, and verified via in vivo study. The resulting model will help for therapy optimization in the clinical setting. Clinically, breast cancer liver metastases can be observed as hypoattenuated in MRI and CT images caused by low penetration of drugs or contrast agents into the lesions along with a high washout rate, which correlates to poor chemotherapeutic response. Nab-PTX is clinically used for treatment of advanced breast tumors, but not for liver metastasis. We designed MSV-nab-PTX, a new nab-PTX delivery system for specifically homing to tumor associated macrophages in the liver. MSV-nab-PTX consists of nab-PTX loaded in porous silicon multistage nanovectors which were previously shown to be efficient in delivering siRNA and other therapeutics. MSV-nab-PTX was evaluated in in vitro, in vivo and in silico models of liver metastasis. Co-culture of breast cancer tumor cells (3D-spheroids) and macrophages was developed and utilized to evaluate the drug efficacy and to study the mechanism of nab-PTX transport. Addition of macrophages in the 3D model significantly increased the efficacy of MSV-nab-PTX, but not nab-PTX, revealing the major role of macrophages in the drug transport into the lesion. Primary mouse and human macrophages were shown to uptake up to 10 ng of PTX/cell in MSV-nab-PTX with no significant effects on their viability, and later release the PTX over 24h. Treatment with MSV-nab-PTX increased chemokine production by tumor cells when compared to nab-PTX, increasing macrophage migration into the tumor sphere by more than 2-fold. Based on these data, we implemented a mathematical model linking drug release and retention from macrophages to project MSV-nAb-PTX efficacy based on the presence of macrophages in tumor biopsies. Simulation of repeat treatment every 3 days showed a significant reduction of tumor size, and was verified by the in vivo data. MSV-nab-PTX as compared to nab-PTX enhanced PTX concentration in the target lesions, increased apoptosis rate and reduced cancer cells proliferation rate, ultimately reducing the tumor size and prolonging the survival of treated mice. This showed that MSV association with macrophages can increase drug efficacy compared to bolus injection, and that it is feasible to reach sustained lesion regression with the macromolecule-bound formulation. The in silico simulations also revealed that the timing interval is crucial for the treatment strategy, and the effect depends on the size and vascularization stage of the lesion. We conclude that an integrated in vitro, in vivo, and in silico framework may be of use to assess response to albumin bound paclitaxel targeted to breast cancer liver metastasis via tumor associated macrophages. Citation Format: Fransisca Leonard, Curtis T. Louis, Pooja Yesantharao, Tomonori Tanei, Jenolyn F. Alexander, Liu Xuewu, Ferrari Mauro, Kenji Yokoi, Hermann B. Frieboes, Biana Godin. Enhancing therapeutic efficacy of albumin bound paclitaxel in breast cancer liver metastasis by homing to tumor associated macrophages: In vitro, in vivo and in silico studies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1324.
