Claudia Pena Murillo | King's College London (original) (raw)

Papers by Claudia Pena Murillo

MP4 file - 752K, 1. Time-lapse microscopy of CAF1 plated onto collagen I showing the diversity of... more MP4 file - 752K, 1. Time-lapse microscopy of CAF1 plated onto collagen I showing the diversity of CAF movement, with a predominance of motile cells with longer tracks. Images were captured every 10 mins and analysed using IMARIS software. The centre of each CAF is marked by a grey square. Migration was visualized by a track that changes colour in time as shown by the scale lower right corner. Examples of highly motile CAF are shown in the left quadrants and less motile CAF at the junction of the upper and lower left quadrants. Quantification of the migration is shown in supplementary Table ST1.

MP4 file - 752K, 1. Time-lapse microscopy of CAF1 plated onto collagen I showing the diversity of... more MP4 file - 752K, 1. Time-lapse microscopy of CAF1 plated onto collagen I showing the diversity of CAF movement, with a predominance of motile cells with longer tracks. Images were captured every 10 mins and analysed using IMARIS software. The centre of each CAF is marked by a grey square. Migration was visualized by a track that changes colour in time as shown by the scale lower right corner. Examples of highly motile CAF are shown in the left quadrants and less motile CAF at the junction of the upper and lower left quadrants. Quantification of the migration is shown in supplementary Table ST1.

PDF file - 79K, Supplementary Table ST2. Quantification of movement parameters of CAF-N and NF.

MP4 file - 1035K, 1. Time-lapse microscopy of NF6 plated onto collagen I showing NF movement, wit... more MP4 file - 1035K, 1. Time-lapse microscopy of NF6 plated onto collagen I showing NF movement, with motile cells with shorter tracks. Images were captured every 10 mins and analysed using IMARIS software. The centre of each CAF is marked by a grey square. Migration was visualized by a track that changes colour in time as shown by the scale lower right corner. Quantification of the migration is shown in supplementary Table ST1.

PDF file - 2707K, Fig. S1. Phenotypical characterization of CAF, DAF and NF used in the study. Fi... more PDF file - 2707K, Fig. S1. Phenotypical characterization of CAF, DAF and NF used in the study. Fig. S2. Expression of known gene expression markers of CAFs at mRNA level. Fig. S3. Validation of microarray data at the protein level. Fig. S4. Invasion of transformed human oral keratinocytes in 3D constructs depends on the type of fibroblasts embedded in the collagen biomatrix. Fig. S5. Quantification of growth factor synthesis by CAF and NF maintained in 2D cultures and 3D constructs. Fig. S6. Quantification of RhoA-GTPase and Rac1/2/3-GTPase in CAF-N and NF. Fig. S7. Visualization of the pattern of distribution of hyaluronic acid (HA) in patient samples and 3D constructs with alcian blue staining. Fig. S8. Quantification of HAS2 mRNA levels in HAS2 shRNA (h) lentiviral transduced CAF.

University of North Carolina at Chapel Hill - Carolina Digital Repository, 2022

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Journal of Clinical Oncology, 2010

Purpose To identify functionally related prognostic gene sets for head and neck squamous cell car... more Purpose To identify functionally related prognostic gene sets for head and neck squamous cell carcinoma (HNSCC) by unsupervised statistical analysis of microarray data. Patients and Methods Microarray analysis was performed on 14 normal oral epithelium and 71 HNSCCs from patients with outcome data. Spectral clustering (SC) analysis of the data set identified multiple vectors representing distinct aspects of gene expression heterogeneity between samples. Gene ontology (GO) analysis of vector gene lists identified gene sets significantly enriched within defined biologic pathways. The prognostic significance of these was established by Cox survival analysis. Results The most influential SC vectors were V2 and V3. V2 separated normal from tumor samples. GO analysis of V2 gene lists identified pathways with heterogeneous expression between HNSCCs, notably focal adhesion (FA)/extracellular matrix remodeling and cytokine-cytokine receptor (CR) interactions. Similar analysis of V3 gene list...

Cancers

Real-world studies have suggested decreased trastuzumab emtansine (T-DM1) effectiveness in patien... more Real-world studies have suggested decreased trastuzumab emtansine (T-DM1) effectiveness in patients with metastatic breast cancer (mBC) who received prior trastuzumab plus pertuzumab (H + P). However, these studies may have been biased toward pertuzumab-experienced patients with more aggressive disease. Using an electronic health record-derived database, patients diagnosed with mBC on/after 1 January 2011 who initiated T-DM1 in any treatment line (primary cohort) or who initiated second-line T-DM1 following first-line H ± P (secondary cohort) from 22 February 2013 to 31 December 2019 were included. The primary outcome was time from index date to next treatment or death (TTNT). In the primary cohort (n = 757), the percentage of patients with prior P increased from 37% to 73% across the study period, while population characteristics and treatment effectiveness measures were generally stable. Among P-experienced patients from the secondary cohort (n = 246), median time from mBC diagnos...

Molecular Cancer Therapeutics, 2011

Background: One component of the therapeutic efficacy of IgG1 monoclonal antibodies (mAb) is thei... more Background: One component of the therapeutic efficacy of IgG1 monoclonal antibodies (mAb) is their ability to induce antibody dependent cellular cytotoxicity (ADCC) by NK cells and other immune effectors bearing the low-affinity Fc RIIIa (CD16) receptor. Clinical studies establish the relevance of ADCC finding widespread polymorphisms that encode a very low affinity CD16 (158F/F) predict limited clinical responses to Cetuximab or Rituximab. Now, mAbs with increased affinity for CD16 can be produced using GlycoMab technology. The altered glycosylation pattern in the Fc domain of these antibodies enhances CD16-binding and ADCC irrespective of genotype. Yet, the potential for enhanced ADCC in patients with advanced colorectal carcinoma (CRC) has not been demonstrated. Considering the potential for tumor-associated immune impairments and treatments-associated leukopenia, we enumerated and characterized NK cells from patients prior to chemotherapy, on active therapy, or following two-lin...

British Journal of Cancer, 2014

Background: The epidermal growth factor receptor (EGFR) is overexpressed in colorectal cancer (CR... more Background: The epidermal growth factor receptor (EGFR) is overexpressed in colorectal cancer (CRC), and is correlated with poor prognosis, making it an attractive target for monoclonal antibody (mAb) therapy. A component of the therapeutic efficacy of IgG1 mAbs is their stimulation of antibody-dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells bearing the CD16 receptor. As NK cells are functionally impaired in cancer patients and may be further compromised upon chemotherapy, it is crucial to assess whether immunotherapeutic strategies aimed at further enhancing ADCC are viable. Methods: CRC patients before, during and after chemotherapy were immunophenotyped by flow cytometry for major white blood cell populations. ADCC-independent NK cell functionality was assessed in cytotoxicity assays against K562 cells. ADCC-dependent killing of EGFR þ A431 cancer cells by NK cells was measured with a degranulation assay where ADCC was induced by GA201, an anti-EGFR mAb glyco-engineered to enhance ADCC. Results: Here, we confirm the observation that NK cells in cancer patients are dysfunctional. However, GA201 was able to induce robust NK cell-dependent cytotoxicity in CRC patient NK cells, effectively overcoming their impairment. Conclusions: These findings support the evaluation of the therapeutic potential of GA201 in combination with chemotherapy in CRC patients. Colorectal cancer (CRC) is the second most frequent cause of cancer death in the western world. In the United States alone, the American Cancer Society estimates more than 140 000 new cases and 50 000 deaths for 2013. Overall, the lifetime risk of developing CRC is 5.1% (American Cancer Society, 2013). A modest increase in average survival can be achieved with current therapeutic strategies, yielding 10-12 months with single agent 5-fluorouracil and increasing to 16-20 months upon addition of oxaliplatin and irinotecan, compared with 6 months with palliative care alone. When administered as a first-line treatment, combination chemotherapy can substantially improve response rates (31%-56%), median progression-free survival (6.5-9 months) and median

Oral Oncology Supplement, 2007

Oral and Symposium abstracts, Friday 18 May 63 and subsequent malignancy were 41% gingiva or vest... more Oral and Symposium abstracts, Friday 18 May 63 and subsequent malignancy were 41% gingiva or vestibule, 32% ventral tongue, 14% dorsum tongue, 14% buccal mucosa. 50% of these arose in a background of Erosive oral lichen planus, 27% in relation to the reticular form of LP and 14% associated with the atypical form. We present a follow up of this case series.

British Journal of Cancer, 2012

BACKGROUND: Locoregional recurrence is the major cause of treatment failure after surgery for ora... more BACKGROUND: Locoregional recurrence is the major cause of treatment failure after surgery for oral squamous cell carcinoma. Molecular diagnostics have the potential to improve on clinicopathological parameters to predict this recurrence and plan adjuvant treatment. The test most frequently applied is based on detecting TP53 mutations, but alternative methodology is required for cases that harbour the wild-type gene. METHODS: One hundred and two cases with tumour-adjacent margins, considered to be clear margins by microscopy, were examined using carefully optimised molecular diagnostics based on detection of the TP53 and Ly-6D markers. The markers were also combined to provide a dual approach. RESULTS: The dual molecular diagnostic identified cases with a significant increase in the probablility of developing locoregional recurrence when tumour-adjacent positive and clear margins were compared (P ¼ 0.0001). These tests were most useful when the clearance at the resection margins was 5 mm or less. The TP53-based diagnostic was a better predictor of locoregional recurrence than established clinicopathological parameters. CONCLUSION: The optimised TP53-based diagnostic rapidly identifies an important subgroup of cases with close margins that will benefit from new treatment modalities to reduce the risk of recurrence.

1039 Background: KAMILLA is an open-label, single-arm, phase 3b safety study of T-DM1 in pts with... more 1039 Background: KAMILLA is an open-label, single-arm, phase 3b safety study of T-DM1 in pts with HER2-positive advanced BC (NCT01702571). The treated (safety) population of KAMILLA comprises 2 cohorts: a larger global Cohort 1 (n=2002) and a smaller Asia Cohort 2 (n=181 [China, n=154; Thailand, n=15; Indonesia, n=12]). Here we report results from Cohort 2 in the context of those previously reported for Cohort 1. Methods: Pts had HER2-positive, locally advanced or mBC with progression after chemotherapy and anti-HER2 therapy or ≤6 months (mo) of completing adjuvant therapy. T-DM1 3.6 mg/kg was given intravenously every 3 weeks until disease progression, consent withdrawal, or unacceptable toxicity. Primary endpoints were grade ≥3 (G≥3) adverse events of primary interest (AEPIs), specifically hepatic events, allergic reactions, thrombocytopenia (TCP), and hemorrhage events; all other G≥3 treatment-related AEs (TRAEs); and all-grade pneumonitis. Results: As of 31 July 2019,KAMILLA enr...

Heterogeneity of carcinoma-associated fibroblasts (CAF) has long been recognized, but the functio... more Heterogeneity of carcinoma-associated fibroblasts (CAF) has long been recognized, but the functional significance remains poorly understood. Here, we report the distinction of two CAF subtypes in oral squamous cell carcinoma (OSCC) that have differential tumor-promoting capability, one with a transcriptome and secretome closer to normal fibroblasts (CAF-N) and the other with a more divergent expression pattern (CAF-D). Both subtypes supported higher tumor incidence in nonobese diabetic/severe combined immunodeficient (NOD/SCID) Ilg2(null) mice and deeper invasion of malignant keratinocytes than normal or dysplasiaassociated fibroblasts, but CAF-N was more efficient than CAF-D in enhancing tumor incidence. CAF-N included more intrinsically motile fibroblasts maintained by high autocrine production of hyaluronan. Inhibiting CAF-N migration by blocking hyaluronan synthesis or chain elongation impaired invasion of adjacent OSCC cells, pinpointing fibroblast motility as an essential mechanism in this process. In contrast, CAF-D harbored fewer motile fibroblasts but synthesized higher TGF-b1 levels. TGF-b1 did not stimulate CAF-D migration but enhanced invasion and expression of epithelial-mesenchymal transition (EMT) markers in malignant keratinocytes. Inhibiting TGF-b1 in three-dimensional cultures containing CAF-D impaired keratinocyte invasion, suggesting TGF-b1-induced EMT mediates CAF-D-induced carcinoma cell invasion. TGF-b1-pretreated normal fibroblasts also induced invasive properties in transformed oral keratinocytes, indicating that TGF-b1-synthesizing fibroblasts, as well as hyaluronan-synthesizing fibroblasts, are critical for carcinoma invasion. Taken together, these results discern two subtypes of CAF that promote OSCC cell invasion via different mechanisms. Cancer Res; 73(13); 3888-901. Ó2013 AACR.

Cancer Research, 2013

Heterogeneity of carcinoma-associated fibroblasts (CAF) has long been recognized, but the functio... more Heterogeneity of carcinoma-associated fibroblasts (CAF) has long been recognized, but the functional significance remains poorly understood. Here, we report the distinction of two CAF subtypes in oral squamous cell carcinoma (OSCC) that have differential tumor-promoting capability, one with a transcriptome and secretome closer to normal fibroblasts (CAF-N) and the other with a more divergent expression pattern (CAF-D). Both subtypes supported higher tumor incidence in nonobese diabetic/severe combined immunodeficient (NOD/SCID) Ilγ2(null) mice and deeper invasion of malignant keratinocytes than normal or dysplasia-associated fibroblasts, but CAF-N was more efficient than CAF-D in enhancing tumor incidence. CAF-N included more intrinsically motile fibroblasts maintained by high autocrine production of hyaluronan. Inhibiting CAF-N migration by blocking hyaluronan synthesis or chain elongation impaired invasion of adjacent OSCC cells, pinpointing fibroblast motility as an essential mechanism in this process. In contrast, CAF-D harbored fewer motile fibroblasts but synthesized higher TGF-β1 levels. TGF-β1 did not stimulate CAF-D migration but enhanced invasion and expression of epithelial-mesenchymal transition (EMT) markers in malignant keratinocytes. Inhibiting TGF-β1 in three-dimensional cultures containing CAF-D impaired keratinocyte invasion, suggesting TGF-β1-induced EMT mediates CAF-D-induced carcinoma cell invasion. TGF-β1-pretreated normal fibroblasts also induced invasive properties in transformed oral keratinocytes, indicating that TGF-β1-synthesizing fibroblasts, as well as hyaluronan-synthesizing fibroblasts, are critical for carcinoma invasion. Taken together, these results discern two subtypes of CAF that promote OSCC cell invasion via different mechanisms.

British Journal of Oral & Maxillofacial Surgery, 2007

... Affiliations. Guy's, King's and St Thomas' Hospitals, London, Unit... more ... Affiliations. Guy's, King's and St Thomas' Hospitals, London, United Kingdom. ,; Andrew Brown: Affiliations. Queen Victoria Hospital, East Grinstead, United Kingdom. ,; Kenneth Lavery: Affiliations. Queen Victoria Hospital, East Grinstead, United Kingdom. ,; John Tighe: Affiliations ...

MP4 file - 752K, 1. Time-lapse microscopy of CAF1 plated onto collagen I showing the diversity of... more MP4 file - 752K, 1. Time-lapse microscopy of CAF1 plated onto collagen I showing the diversity of CAF movement, with a predominance of motile cells with longer tracks. Images were captured every 10 mins and analysed using IMARIS software. The centre of each CAF is marked by a grey square. Migration was visualized by a track that changes colour in time as shown by the scale lower right corner. Examples of highly motile CAF are shown in the left quadrants and less motile CAF at the junction of the upper and lower left quadrants. Quantification of the migration is shown in supplementary Table ST1.

MP4 file - 752K, 1. Time-lapse microscopy of CAF1 plated onto collagen I showing the diversity of... more MP4 file - 752K, 1. Time-lapse microscopy of CAF1 plated onto collagen I showing the diversity of CAF movement, with a predominance of motile cells with longer tracks. Images were captured every 10 mins and analysed using IMARIS software. The centre of each CAF is marked by a grey square. Migration was visualized by a track that changes colour in time as shown by the scale lower right corner. Examples of highly motile CAF are shown in the left quadrants and less motile CAF at the junction of the upper and lower left quadrants. Quantification of the migration is shown in supplementary Table ST1.

PDF file - 79K, Supplementary Table ST2. Quantification of movement parameters of CAF-N and NF.

MP4 file - 1035K, 1. Time-lapse microscopy of NF6 plated onto collagen I showing NF movement, wit... more MP4 file - 1035K, 1. Time-lapse microscopy of NF6 plated onto collagen I showing NF movement, with motile cells with shorter tracks. Images were captured every 10 mins and analysed using IMARIS software. The centre of each CAF is marked by a grey square. Migration was visualized by a track that changes colour in time as shown by the scale lower right corner. Quantification of the migration is shown in supplementary Table ST1.

PDF file - 2707K, Fig. S1. Phenotypical characterization of CAF, DAF and NF used in the study. Fi... more PDF file - 2707K, Fig. S1. Phenotypical characterization of CAF, DAF and NF used in the study. Fig. S2. Expression of known gene expression markers of CAFs at mRNA level. Fig. S3. Validation of microarray data at the protein level. Fig. S4. Invasion of transformed human oral keratinocytes in 3D constructs depends on the type of fibroblasts embedded in the collagen biomatrix. Fig. S5. Quantification of growth factor synthesis by CAF and NF maintained in 2D cultures and 3D constructs. Fig. S6. Quantification of RhoA-GTPase and Rac1/2/3-GTPase in CAF-N and NF. Fig. S7. Visualization of the pattern of distribution of hyaluronic acid (HA) in patient samples and 3D constructs with alcian blue staining. Fig. S8. Quantification of HAS2 mRNA levels in HAS2 shRNA (h) lentiviral transduced CAF.

University of North Carolina at Chapel Hill - Carolina Digital Repository, 2022

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Journal of Clinical Oncology, 2010

Purpose To identify functionally related prognostic gene sets for head and neck squamous cell car... more Purpose To identify functionally related prognostic gene sets for head and neck squamous cell carcinoma (HNSCC) by unsupervised statistical analysis of microarray data. Patients and Methods Microarray analysis was performed on 14 normal oral epithelium and 71 HNSCCs from patients with outcome data. Spectral clustering (SC) analysis of the data set identified multiple vectors representing distinct aspects of gene expression heterogeneity between samples. Gene ontology (GO) analysis of vector gene lists identified gene sets significantly enriched within defined biologic pathways. The prognostic significance of these was established by Cox survival analysis. Results The most influential SC vectors were V2 and V3. V2 separated normal from tumor samples. GO analysis of V2 gene lists identified pathways with heterogeneous expression between HNSCCs, notably focal adhesion (FA)/extracellular matrix remodeling and cytokine-cytokine receptor (CR) interactions. Similar analysis of V3 gene list...

Cancers

Real-world studies have suggested decreased trastuzumab emtansine (T-DM1) effectiveness in patien... more Real-world studies have suggested decreased trastuzumab emtansine (T-DM1) effectiveness in patients with metastatic breast cancer (mBC) who received prior trastuzumab plus pertuzumab (H + P). However, these studies may have been biased toward pertuzumab-experienced patients with more aggressive disease. Using an electronic health record-derived database, patients diagnosed with mBC on/after 1 January 2011 who initiated T-DM1 in any treatment line (primary cohort) or who initiated second-line T-DM1 following first-line H ± P (secondary cohort) from 22 February 2013 to 31 December 2019 were included. The primary outcome was time from index date to next treatment or death (TTNT). In the primary cohort (n = 757), the percentage of patients with prior P increased from 37% to 73% across the study period, while population characteristics and treatment effectiveness measures were generally stable. Among P-experienced patients from the secondary cohort (n = 246), median time from mBC diagnos...

Molecular Cancer Therapeutics, 2011

Background: One component of the therapeutic efficacy of IgG1 monoclonal antibodies (mAb) is thei... more Background: One component of the therapeutic efficacy of IgG1 monoclonal antibodies (mAb) is their ability to induce antibody dependent cellular cytotoxicity (ADCC) by NK cells and other immune effectors bearing the low-affinity Fc RIIIa (CD16) receptor. Clinical studies establish the relevance of ADCC finding widespread polymorphisms that encode a very low affinity CD16 (158F/F) predict limited clinical responses to Cetuximab or Rituximab. Now, mAbs with increased affinity for CD16 can be produced using GlycoMab technology. The altered glycosylation pattern in the Fc domain of these antibodies enhances CD16-binding and ADCC irrespective of genotype. Yet, the potential for enhanced ADCC in patients with advanced colorectal carcinoma (CRC) has not been demonstrated. Considering the potential for tumor-associated immune impairments and treatments-associated leukopenia, we enumerated and characterized NK cells from patients prior to chemotherapy, on active therapy, or following two-lin...

British Journal of Cancer, 2014

Background: The epidermal growth factor receptor (EGFR) is overexpressed in colorectal cancer (CR... more Background: The epidermal growth factor receptor (EGFR) is overexpressed in colorectal cancer (CRC), and is correlated with poor prognosis, making it an attractive target for monoclonal antibody (mAb) therapy. A component of the therapeutic efficacy of IgG1 mAbs is their stimulation of antibody-dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells bearing the CD16 receptor. As NK cells are functionally impaired in cancer patients and may be further compromised upon chemotherapy, it is crucial to assess whether immunotherapeutic strategies aimed at further enhancing ADCC are viable. Methods: CRC patients before, during and after chemotherapy were immunophenotyped by flow cytometry for major white blood cell populations. ADCC-independent NK cell functionality was assessed in cytotoxicity assays against K562 cells. ADCC-dependent killing of EGFR þ A431 cancer cells by NK cells was measured with a degranulation assay where ADCC was induced by GA201, an anti-EGFR mAb glyco-engineered to enhance ADCC. Results: Here, we confirm the observation that NK cells in cancer patients are dysfunctional. However, GA201 was able to induce robust NK cell-dependent cytotoxicity in CRC patient NK cells, effectively overcoming their impairment. Conclusions: These findings support the evaluation of the therapeutic potential of GA201 in combination with chemotherapy in CRC patients. Colorectal cancer (CRC) is the second most frequent cause of cancer death in the western world. In the United States alone, the American Cancer Society estimates more than 140 000 new cases and 50 000 deaths for 2013. Overall, the lifetime risk of developing CRC is 5.1% (American Cancer Society, 2013). A modest increase in average survival can be achieved with current therapeutic strategies, yielding 10-12 months with single agent 5-fluorouracil and increasing to 16-20 months upon addition of oxaliplatin and irinotecan, compared with 6 months with palliative care alone. When administered as a first-line treatment, combination chemotherapy can substantially improve response rates (31%-56%), median progression-free survival (6.5-9 months) and median

Oral Oncology Supplement, 2007

Oral and Symposium abstracts, Friday 18 May 63 and subsequent malignancy were 41% gingiva or vest... more Oral and Symposium abstracts, Friday 18 May 63 and subsequent malignancy were 41% gingiva or vestibule, 32% ventral tongue, 14% dorsum tongue, 14% buccal mucosa. 50% of these arose in a background of Erosive oral lichen planus, 27% in relation to the reticular form of LP and 14% associated with the atypical form. We present a follow up of this case series.

British Journal of Cancer, 2012

BACKGROUND: Locoregional recurrence is the major cause of treatment failure after surgery for ora... more BACKGROUND: Locoregional recurrence is the major cause of treatment failure after surgery for oral squamous cell carcinoma. Molecular diagnostics have the potential to improve on clinicopathological parameters to predict this recurrence and plan adjuvant treatment. The test most frequently applied is based on detecting TP53 mutations, but alternative methodology is required for cases that harbour the wild-type gene. METHODS: One hundred and two cases with tumour-adjacent margins, considered to be clear margins by microscopy, were examined using carefully optimised molecular diagnostics based on detection of the TP53 and Ly-6D markers. The markers were also combined to provide a dual approach. RESULTS: The dual molecular diagnostic identified cases with a significant increase in the probablility of developing locoregional recurrence when tumour-adjacent positive and clear margins were compared (P ¼ 0.0001). These tests were most useful when the clearance at the resection margins was 5 mm or less. The TP53-based diagnostic was a better predictor of locoregional recurrence than established clinicopathological parameters. CONCLUSION: The optimised TP53-based diagnostic rapidly identifies an important subgroup of cases with close margins that will benefit from new treatment modalities to reduce the risk of recurrence.

1039 Background: KAMILLA is an open-label, single-arm, phase 3b safety study of T-DM1 in pts with... more 1039 Background: KAMILLA is an open-label, single-arm, phase 3b safety study of T-DM1 in pts with HER2-positive advanced BC (NCT01702571). The treated (safety) population of KAMILLA comprises 2 cohorts: a larger global Cohort 1 (n=2002) and a smaller Asia Cohort 2 (n=181 [China, n=154; Thailand, n=15; Indonesia, n=12]). Here we report results from Cohort 2 in the context of those previously reported for Cohort 1. Methods: Pts had HER2-positive, locally advanced or mBC with progression after chemotherapy and anti-HER2 therapy or ≤6 months (mo) of completing adjuvant therapy. T-DM1 3.6 mg/kg was given intravenously every 3 weeks until disease progression, consent withdrawal, or unacceptable toxicity. Primary endpoints were grade ≥3 (G≥3) adverse events of primary interest (AEPIs), specifically hepatic events, allergic reactions, thrombocytopenia (TCP), and hemorrhage events; all other G≥3 treatment-related AEs (TRAEs); and all-grade pneumonitis. Results: As of 31 July 2019,KAMILLA enr...

Heterogeneity of carcinoma-associated fibroblasts (CAF) has long been recognized, but the functio... more Heterogeneity of carcinoma-associated fibroblasts (CAF) has long been recognized, but the functional significance remains poorly understood. Here, we report the distinction of two CAF subtypes in oral squamous cell carcinoma (OSCC) that have differential tumor-promoting capability, one with a transcriptome and secretome closer to normal fibroblasts (CAF-N) and the other with a more divergent expression pattern (CAF-D). Both subtypes supported higher tumor incidence in nonobese diabetic/severe combined immunodeficient (NOD/SCID) Ilg2(null) mice and deeper invasion of malignant keratinocytes than normal or dysplasiaassociated fibroblasts, but CAF-N was more efficient than CAF-D in enhancing tumor incidence. CAF-N included more intrinsically motile fibroblasts maintained by high autocrine production of hyaluronan. Inhibiting CAF-N migration by blocking hyaluronan synthesis or chain elongation impaired invasion of adjacent OSCC cells, pinpointing fibroblast motility as an essential mechanism in this process. In contrast, CAF-D harbored fewer motile fibroblasts but synthesized higher TGF-b1 levels. TGF-b1 did not stimulate CAF-D migration but enhanced invasion and expression of epithelial-mesenchymal transition (EMT) markers in malignant keratinocytes. Inhibiting TGF-b1 in three-dimensional cultures containing CAF-D impaired keratinocyte invasion, suggesting TGF-b1-induced EMT mediates CAF-D-induced carcinoma cell invasion. TGF-b1-pretreated normal fibroblasts also induced invasive properties in transformed oral keratinocytes, indicating that TGF-b1-synthesizing fibroblasts, as well as hyaluronan-synthesizing fibroblasts, are critical for carcinoma invasion. Taken together, these results discern two subtypes of CAF that promote OSCC cell invasion via different mechanisms. Cancer Res; 73(13); 3888-901. Ó2013 AACR.

Cancer Research, 2013

Heterogeneity of carcinoma-associated fibroblasts (CAF) has long been recognized, but the functio... more Heterogeneity of carcinoma-associated fibroblasts (CAF) has long been recognized, but the functional significance remains poorly understood. Here, we report the distinction of two CAF subtypes in oral squamous cell carcinoma (OSCC) that have differential tumor-promoting capability, one with a transcriptome and secretome closer to normal fibroblasts (CAF-N) and the other with a more divergent expression pattern (CAF-D). Both subtypes supported higher tumor incidence in nonobese diabetic/severe combined immunodeficient (NOD/SCID) Ilγ2(null) mice and deeper invasion of malignant keratinocytes than normal or dysplasia-associated fibroblasts, but CAF-N was more efficient than CAF-D in enhancing tumor incidence. CAF-N included more intrinsically motile fibroblasts maintained by high autocrine production of hyaluronan. Inhibiting CAF-N migration by blocking hyaluronan synthesis or chain elongation impaired invasion of adjacent OSCC cells, pinpointing fibroblast motility as an essential mechanism in this process. In contrast, CAF-D harbored fewer motile fibroblasts but synthesized higher TGF-β1 levels. TGF-β1 did not stimulate CAF-D migration but enhanced invasion and expression of epithelial-mesenchymal transition (EMT) markers in malignant keratinocytes. Inhibiting TGF-β1 in three-dimensional cultures containing CAF-D impaired keratinocyte invasion, suggesting TGF-β1-induced EMT mediates CAF-D-induced carcinoma cell invasion. TGF-β1-pretreated normal fibroblasts also induced invasive properties in transformed oral keratinocytes, indicating that TGF-β1-synthesizing fibroblasts, as well as hyaluronan-synthesizing fibroblasts, are critical for carcinoma invasion. Taken together, these results discern two subtypes of CAF that promote OSCC cell invasion via different mechanisms.

British Journal of Oral & Maxillofacial Surgery, 2007

... Affiliations. Guy's, King's and St Thomas' Hospitals, London, Unit... more ... Affiliations. Guy's, King's and St Thomas' Hospitals, London, United Kingdom. ,; Andrew Brown: Affiliations. Queen Victoria Hospital, East Grinstead, United Kingdom. ,; Kenneth Lavery: Affiliations. Queen Victoria Hospital, East Grinstead, United Kingdom. ,; John Tighe: Affiliations ...