Henry P. Foote’s research while affiliated with University of North Carolina at Chapel Hill and other places

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Publications (5)


Fig. 3 | Engineered liver metastases are comparable to liver metastases found in vivo. a, Engineered HT-29 liver metastases (left), liver metastases formed following intrasplenic injection of HT-29 cells (middle) and liver metastases biopsied from late-stage human CRC patients (right) all demonstrate classic histologic features of liver metastases of gastrointestinal origin. Experiments were repeated four times independently with similar results. Scale bars, 20 µ m. b, Hierarchal cluster analysis of average global gene expression patterns displayed by HT-29 cells grown on plastic, Matrigel, liver BMSs ('Engineered liver metastases') and in vivo liver metastases derived from intrasplenic injection of HT-29 cells ('In vivo liver metastases') (n = 4 biologically independent samples). 
Fig. 4 | Engineered metastases demonstrate increased metastatic potential in vivo. a-d, Bioluminescence images of animals 30 days post direct hepatic injection (a,b) or tail-vein injection (c,d) with CRC cells isolated from plastic, collagen, Matrigel, liver BMSs and lung BMSs. a,c, HT-29-luc2 cells were used. b,d, CRC119 cells were used. n = 10 biologically independent animals per group. The experiment was repeated twice and the results were pooled. 
Fig. 5 | CRC cells grown on different substratas respond differently to chemotherapeutics and radiotherapy. a, Response of CRC cells grown on plastic, collagen, Matrigel, liver BMSs and lung BMSs to chemotherapeutics (n = 6 biologically independent cell samples). Data represent mean ± s.e.m. Differences in therapeutic responses were determined using a one-way ANOVA with Tukey's multiple comparison post-test. Statistical significance is indicated with letters above (P < 0.05). Groups that share the same letter are not significantly different. b, Response of CRC cells grown on plastic, collagen, Matrigel, liver BMSs and lung BMSs to radiotherapy (n = 3 biologically independent cell samples). Data represent mean ± s.e.m. 
BMSs recapitulate tissue-specific microenvironments found in vivo
a, Schematic depicting methodology used for studying metastatic disease in vitro. b, Scanning electron micrographs of lung and liver BMSs. Scale bars, 100 nm. c, Analysis of growth factors and cytokines present in lung tissues before and after decellularization (n = 4 biologically independent decellularized samples from four different rats). Differences in the relative abundance of signalling molecules were determined using multiple t-tests, two-sided. Data represent mean ± s.e.m.; statistical significance determined using the Holm–Sidak method, with α = 0.05. *p < 0.05 (p = 0.001, 0.00011 and 0.00015 for EGF R, PDGF-AA and PDGF-AB, respectively). d, Heat map comparing the composition and relative abundance of proteins present in liver and lung BMSs (n = 4 biologically independent samples). Hierarchical clustering was performed using z-score normalized label-free quantification intensities. bFGF, basic fibroblast growth factor; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; FGF-4, fibroblast growth factor-4; FGF-6, fibroblast growth factor-6; FGF-7, fibroblast growth factor-7; G-CSF, granulocyte-colony stimulating factor; GDNF, glial-derived neurotrophic factor; GM-CSF, granulocyte macrophage-colony stimulating factor; HB-EGF, heparin-binding epidermal growth factor; IGFBP-1, insulin-like growth factor binding protein 1; IGFBP-3, insulin-like growth factor binding protein 3; IGFBP-4, insulin-like growth factor binding protein 4; IGFBP-6, insulin-like growth factor binding protein 6; IGF-I, insulin-like growth factor-I; IGF-1 SR, insulin-like growth factor-I receptor; IGF-II, insulin-like growth factor-II; M-CSF, macrophage-colony stimulating factor; M-CSF R, macrophage-colony stimulating factor receptor; NT-3, neurotrophin-3; NT-4, neurotrophin-4; PDGF-R α, platelet-derived growth factor receptor alpha; PDGF-R β, platelet-derived growth factor receptor beta; PDGF-AA, platelet-derived growth factor AA; PDGF-AB, platelet-derived growth factor AB; PDGF-BB, platelet-derived growth factor BB; PIGF, phosphatidylinositol glycan anchor biosynthesis class F; SCF, stromal cell-derived factor-1; SCF R, stromal cell-derived factor receptor; TGF-α, transforming growth factor alpha; TGF-β, transforming growth factor beta; TGF-β 2, transforming growth factor beta 2, TGF- β 3, transforming growth factor beta 3; VEGF, vascular endothelial growth factor; VEGF R2, vascular endothelial growth factor receptor 2; VEGF R3, vascular endothelial growth factor receptor 3; VEGF-D, vascular endothelial growth factor receptor D.
CRC cells spontaneously form 3D engineered metastases when cultured on liver and lung BMSs
a, Scanning electron micrographs of HT-29, SW480 and Caco2 cells grown on plastic, collagen, Matrigel, liver BMSs and lung BMSs. Scale bars, 50 µm. Experiments were repeated three times independently with similar results. b,c, Seeding efficiencies (b) and growth rates (c) of HT-29 (left), SW480 (middle) and Caco2 (right) cells seeded on plastic, collagen, Matrigel, liver BMSs and lung BMSs (n = 3 biologically independent cell samples). Data represent mean ± s.e.m. Differences in seeding efficiency and growth rate were determined using a one-way ANOVA with Tukey’s multiple comparison post-test. Statistical significance is indicated with letters above (p < 0.05). Groups that share the same letter are not significantly different (p = 8.19 × 10–5, 0.1043 and 1.07 × 10–5 for HT-29, SW480 and Caco2, respectively).
Organ-specific metastases obtained by culturing colorectal cancer cells on tissue-specific decellularized scaffolds
  • Article
  • Publisher preview available

June 2018

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496 Reads

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81 Citations

Nature Biomedical Engineering

Xi Tian

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Michael E. Werner

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Andrew Z. Wang

Metastatic disease remains the primary cause of mortality in cancer patients. Yet the number of available in vitro models to study metastasis is limited by challenges in the recapitulation of the metastatic microenvironment in vitro, and by difficulties in maintaining colonized-tissue specificity in the expansion and maintenance of metastatic cells. Here, we show that decellularized scaffolds that retain tissue-specific extracellular-matrix components and bound signalling molecules enable, when seeded with colorectal cancer cells, the spontaneous formation of three-dimensional cell colonies that histologically, molecularly and phenotypically resemble in vivo metastases. Lung and liver metastases obtained by culturing colorectal cancer cells on, respectively, lung and liver decellularized scaffolds retained their tissue-specific tropism when injected in mice. We also found that the engineered metastases contained signet ring cells, which has not previously been observed ex vivo. A culture system with tissue-specific decellularized scaffolds represents a simple and powerful approach for the study of organ-specific cancer metastases.

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CRLX101, a Nanoparticle-Drug Conjugate Containing Camptothecin, Improves Rectal Cancer Chemoradiotherapy by Inhibiting DNA Repair and HIF1α

October 2016

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48 Reads

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72 Citations

Cancer Research

Novel agents are needed to improve chemoradiotherapy for locally advanced rectal cancer. In this study, we assessed the ability of CRLX101, an investigational nanoparticle-drug conjugate containing the payload camptothecin (CPT), to improve therapeutic responses as compared to standard chemotherapy. CRLX101 was evaluated as a radiosensitizer in colorectal cancer cell lines and murine xenograft models. CRLX101 was as potent as CPT in vitro in its ability to radiosensitize cancer cells. Evaluations in vivo demonstrated that the addition of CRLX101 to standard chemoradiotherapy significantly increased therapeutic efficacy by inhibiting DNA repair and HIF-1α pathway activation in tumor cells. Notably, CRLX101 was more effective than oxaliplatin at enhancing the efficacy of chemoradiotherapy, with CRLX101 and 5-fluorouracil (5-FU) producing the highest therapeutic efficacy. Gastrointestinal toxicity was also significantly lower for CRLX101 compared to CPT when combined with radiotherapy. Our results offer a preclinical proof of concept for CRLX101 as a modality to improve the outcome of neoadjuvant chemoradiotherapy for rectal cancer treatment, in support of ongoing clinical evaluation of this agent (LCC1315 NCT02010567).


Abstract 4264: Engineered in vitro models of cancer metastasis using decellularized biomatrix

July 2016

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24 Reads

Cancer Research

Background: Metastasis contributes to majority of death in cancer patients. However, cancer metastasis is difficult to study due to the lack of experimental models that can fully recapitulate the biological process, especially the organ specificity of cancer metastasis. Recent advances in tissue engineering demonstrated that decellularized tissue, organs that are denuded of cells, are excellent scaffolds for tissue engineering of complex organs, such as liver and lung. These decellularized organs preserve the organ microenvironment, which is critical in cancer metastasis. We hypothesized that we can utilize decellularized organ and engineer in vitro models of cancer metastasis that can recapitulate the organ specificity of cancer metastasis. Here we report the proof-of-principle of this approach by employing colorectal cancer as a disease model. Since the primary cause of morbidity and mortality in colorectal patients is liver and lung metastasis, we aimed to engineer in vitro models of colorectal cancer lung and liver metastasis. Methods: Decellularized biomatrix was prepared by sodium deoxycholate based perfusion decellularization of rat liver or lung. We compared the growth factors on the biomatrix scaffold to that of normal rat liver and lung using semi-quantitative ELISA. We cultured colorectal cancer cell lines: HT-29, SW480 and Caco2, on tissue culture dishes coated with liver and lung decellularized biomatrix scaffolds. Cell colony morphology and structure was examined by scanning electron microscopy (SEM), transmission electron microscopy (TEM) and hematoxylin and eosin stain. Therapeutic response (chemotherapy and radiation) for cells grown on biomatrix was also examined. Results: Decellularized organs preserved 92% growth factors bound to biomatrix scaffold at near physiological levels. HT-29, SW480 and Caco2 were able to proliferate on dishes coated with biomatrix scaffold and spontaneously formed three-dimensional (3D) colonies when maintained at higher levels. These tumor colonies are millimeter in size and are spherical in shape, similar to in vivo metastases. SEM showed cells on the tumor surface appeared to form tight junctions with each other. TEM images further confirmed that these 3D tumor colonies contain areas of necrosis, consistent existing literature 3D colonies and in vivo metastasis. Importantly, we identified signet ring cell formation in the engineered 3D metastases. We also found the cells in engineered liver and lung metastasis responded to chemotherapy treatment differently than the cells cultured under standard conditions or on collagen or on matrigel. Interestingly, cells in both engineered liver and lung metastasis are more sensitive to radiotherapy than standard condition. Conclusions: Our engineered in vitro tumor metastasis models closely mimic the in vivo metastasis phenotypically, histologically, and biologically. Citation Format: XI TIAN, Michael E. Werner, Henry P. Foote, Ariel D. Hanson, Lola M. Reid, Andrew Z. Wang. Engineered in vitro models of cancer metastasis using decellularized biomatrix. [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 4264.



Abstract 5515: Neoadjuvant chemoradiotherapy for rectal cancer with CRLX101, an investigational nanoparticle-drug conjugate with a camptothecin payload

August 2015

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16 Reads

Cancer Research

Background: There has been great interest in developing novel agents and strategies to improve chemoradiotherapy (CRT) for locally advanced rectal cancer. Irinotecan, a campothecin (CPT) analogue, held high potential, but the combination was clinically infeasible due to severe gastrointestinal toxicities. CRLX101, is an investigational nanoparticle drug conjugate (NDC). Preclinical experiments showed that CRLX101 differentially delivers CPT into cancer cells and appears to durably suppress HIF-1α as well as topoisomerase 1, but with less gastrointestinal toxicities than irinotecan. We therefore hypothesized that the addition of CRLX101 to rectal CRT (5-FU + XRT) may further improve the therapeutic index in this setting. Methods: Synergy with CRLX101 in combination with either XRT or CRT was studied in vitro (SW480 and HT29 colorectal cancer cell lines) and in vivo (murine flank xenograft models). Skin toxicity and hematologic toxicity were also characterized. In order to test the synergy hypothesis in the clinic, a Phase Ib/II clinical trial (LCCC1315) evaluating the addition of CRLX101 to CRT in the neo-adjuvant treatment of rectal cancer is currently underway. A standard 3 + 3 design is being employed for the phase Ib with a CRLX101 starting dose of 12 mg/m² in the first cohort escalating to the CRLX101 monotherapy MTD of 15 mg/m² in the second. The primary phase 2 end-point is the pathological complete response (pCR) rate from treatment. Results: CRLX101 was found to be as potent as camptothecin in vitro. We have demonstrated that CRLX101 functions by inhibition of both DNA repair and HIF-1α signaling. The addition of CRLX101 to radiotherapy increased and prolonged the number of γH2AX foci, even at 24 hours post radiotherapy. We also confirmed that CRLX101 decreased HIF-1α and its downstream targets VEGF and carbonic anhydrase IX in mice bearing HT29 xenografts. Our findings were further validated in vivo: we demonstrated that both CRLX101+5FU+XRT and CRLX101+XRT delayed tumor growth more than other regimens (p-values < 0.05). More importantly, we found CRT with CRLX101+5FU is significantly more effective than CRT with oxaliplatin+5FU (25 days to double tumor volume vs. 11 days), a regimen that has been extensively studied clinically. Preclinical toxicity studies demonstrated that the addition of CRLX101 did not increase hematologic or skin toxicities. In the ongoing clinical trial, none of the first 6 patients enrolled have experienced dose-limiting toxicities, and 1 out of 3 patients who underwent surgery had a pCR. The other 2 patients had extensive treatment response with minimal residual tumor. Conclusions: Preclinical data suggests that CRLX101 improves the therapeutic index of CRT for rectal cancer. Preliminary clinical data is encouraging, and supports further clinical assessment of CRLX101+5FU+XRT in patients with locally advanced rectal cancer. Citation Format: XI TIAN, Minh Nguyen, Henry Foote, Kyle T. Wagner, Hanna K. Sanoff, Autumn J. McRee, Bert H. O'Neil, Benjamin F. Calvo, William A. Blackstock, Joel E. Tepper, Edward Garmey, Scott Eliasof, Andrew Z. Wang. Neoadjuvant chemoradiotherapy for rectal cancer with CRLX101, an investigational nanoparticle-drug conjugate with a camptothecin payload. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5515. doi:10.1158/1538-7445.AM2015-5515

Citations (3)


... For example, collagens, the main structural elements of ECM protein, could efficiently improve the metastasis, self-renewal, proportion, and drug resistance of CSCs [25]. Thus, acellular tissue materials composed of ECM components, including fibrous proteins, glycosaminoglycans, proteoglycans, and sequestered growth factors, have attracted more attention in the field of 3D CSC culture [26,27]. In addition, scaffolds based on ECM have been employed in tissue regeneration, such as wound regeneration [28], peripheral nerve regeneration [29], and so on [30]. ...

Reference:

Thermo-Responsive Hydrogel Based on Lung Decellularized Extracellular Matrix for 3D Culture Model to Enhance Cancer Stem Cell Characteristics
Organ-specific metastases obtained by culturing colorectal cancer cells on tissue-specific decellularized scaffolds

Nature Biomedical Engineering

... Furthermore, CRLX101, a novel nanoparticle-drug conjugate, demonstrated the capacity to selectively deliver camptothecin to cancer cells, thereby sustaining the inhibition of HIF-1α. In preclinical models of rectal cancer, the combination of CRLX101 and anti-angiogenesis drugs such as bevacizumab (Avastin) has been observed to exhibit a notable synergistic effect [151]. SENP-1 is a SUMOylation-specific protease that has the capacity to remove SUMO modifications from substrate proteins in an overly specific manner [152]. ...

CRLX101, a Nanoparticle-Drug Conjugate Containing Camptothecin, Improves Rectal Cancer Chemoradiotherapy by Inhibiting DNA Repair and HIF1α
  • Citing Article
  • October 2016

Cancer Research

... Prior studies showed EP0057 efficacy in recurrent or persistent, epithelial ovarian, fallopian tube or colorectal, peritoneal, and gastroesophageal cancer [111,112], where it showed promising results [112]. Ongoing clinical trials are designed to evaluate the efficacy and safety (Phase 1/2) of this therapeutic in lung [102], gastric [113] and ovarian [103] cancer in combination with Olaparib, as well as to evaluate its pharmacokinetics properties (PK) [102,114] using a population model. ...

CRLX101, an Investigational Nanoparticle Drug Conjugate of Camptothecin, as a Potentially Effective Radiosensitizer in Chemoradiation Treatment of Colorectal Cancer
  • Citing Article
  • November 2015

International Journal of Radiation Oncology*Biology*Physics