Doxycycline-Induced Changes in Circulating MMP or TIMP2 Levels Are Not Associated with Skeletal-Related Event-Free or Overall Survival in Patients with Bone Metastases from Breast Cancer
Doxycycline is often used as a promoter of inducible gene expression in preclinical models; however, it can also have direct effects on tumor growth and survival. This is due in part to its ability to inhibit cell invasion and regulate matrix metalloproteinase (MMP) expression. Given that doxycyclin...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-01-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/15/3/571 |
| _version_ | 1797625065890643968 |
|---|---|
| author | Huijun Zhao Gregory Pond Demetrios Simos Zhou Wang Susan Robertson Gurmit Singh Lisa Vandermeer Mark Clemons Christina Lynn Addison |
| author_facet | Huijun Zhao Gregory Pond Demetrios Simos Zhou Wang Susan Robertson Gurmit Singh Lisa Vandermeer Mark Clemons Christina Lynn Addison |
| author_sort | Huijun Zhao |
| collection | DOAJ |
| description | Doxycycline is often used as a promoter of inducible gene expression in preclinical models; however, it can also have direct effects on tumor growth and survival. This is due in part to its ability to inhibit cell invasion and regulate matrix metalloproteinase (MMP) expression. Given that doxycycline is also osteotropic, a clinical study to assess its effects on modulation of tumor progression or prevention of skeletal-related events (SRE) in patients with bone metastases from breast cancer (the Achilles trial) was undertaken. Patients received 100 mg of oral doxycycline twice daily for 12 weeks, with serum obtained at baseline and 4, 8 and 12 weeks post-initiation of doxycycline treatment. Exploratory analysis of the effects of doxycycline on circulating levels of MMP or tissue inhibitor of matrix metalloproteinase 2 (TIMP2) was performed in enrolled patients. Statistically significant associations were observed between MMP2, MMP9 and TIMP2 at baseline with significant associations maintained between absolute levels and changes in levels of MMP2 and TIMP2 at weeks 4–12 post initiation of doxycycline. Treatment with doxycycline generally resulted in decreases in MMP2 and MMP9 levels with concurrent upregulation of TIMP2 at 12 weeks post-initiation of doxycycline treatment. Despite this, we observed no association with the levels of any of these factors with either SRE-free or overall survival in this patient cohort. In summary, despite observing hypothesized effects of doxycycline administration on surrogate markers of its anti-tumor activity, measures of circulating levels of these biomarkers were not prognostic in this patient population. |
| first_indexed | 2024-03-11T09:51:33Z |
| format | Article |
| id | doaj.art-e81f2e9183234e7383a4f3650973995b |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T09:51:33Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-e81f2e9183234e7383a4f3650973995b2023-11-16T16:14:07ZengMDPI AGCancers2072-66942023-01-0115357110.3390/cancers15030571Doxycycline-Induced Changes in Circulating MMP or TIMP2 Levels Are Not Associated with Skeletal-Related Event-Free or Overall Survival in Patients with Bone Metastases from Breast CancerHuijun Zhao0Gregory Pond1Demetrios Simos2Zhou Wang3Susan Robertson4Gurmit Singh5Lisa Vandermeer6Mark Clemons7Christina Lynn Addison8Program for Cancer Therapeutics, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6, CanadaDepartment of Oncology, McMaster University, 699 Concession Street, Hamilton, ON L8V 5C2, CanadaDivision of Medical Oncology, Department of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 4M5, CanadaProgram for Cancer Therapeutics, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6, CanadaDepartment of Pathology and Laboratory Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 4M5, CanadaDepartment of Pathology and Molecular Medicine, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4L8, CanadaProgram for Cancer Therapeutics, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6, CanadaProgram for Cancer Therapeutics, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6, CanadaProgram for Cancer Therapeutics, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6, CanadaDoxycycline is often used as a promoter of inducible gene expression in preclinical models; however, it can also have direct effects on tumor growth and survival. This is due in part to its ability to inhibit cell invasion and regulate matrix metalloproteinase (MMP) expression. Given that doxycycline is also osteotropic, a clinical study to assess its effects on modulation of tumor progression or prevention of skeletal-related events (SRE) in patients with bone metastases from breast cancer (the Achilles trial) was undertaken. Patients received 100 mg of oral doxycycline twice daily for 12 weeks, with serum obtained at baseline and 4, 8 and 12 weeks post-initiation of doxycycline treatment. Exploratory analysis of the effects of doxycycline on circulating levels of MMP or tissue inhibitor of matrix metalloproteinase 2 (TIMP2) was performed in enrolled patients. Statistically significant associations were observed between MMP2, MMP9 and TIMP2 at baseline with significant associations maintained between absolute levels and changes in levels of MMP2 and TIMP2 at weeks 4–12 post initiation of doxycycline. Treatment with doxycycline generally resulted in decreases in MMP2 and MMP9 levels with concurrent upregulation of TIMP2 at 12 weeks post-initiation of doxycycline treatment. Despite this, we observed no association with the levels of any of these factors with either SRE-free or overall survival in this patient cohort. In summary, despite observing hypothesized effects of doxycycline administration on surrogate markers of its anti-tumor activity, measures of circulating levels of these biomarkers were not prognostic in this patient population.https://www.mdpi.com/2072-6694/15/3/571doxycyclinebreast cancerbone metastasismatrix metalloproteinaseMMP2MMP9 |
| spellingShingle | Huijun Zhao Gregory Pond Demetrios Simos Zhou Wang Susan Robertson Gurmit Singh Lisa Vandermeer Mark Clemons Christina Lynn Addison Doxycycline-Induced Changes in Circulating MMP or TIMP2 Levels Are Not Associated with Skeletal-Related Event-Free or Overall Survival in Patients with Bone Metastases from Breast Cancer Cancers doxycycline breast cancer bone metastasis matrix metalloproteinase MMP2 MMP9 |
| title | Doxycycline-Induced Changes in Circulating MMP or TIMP2 Levels Are Not Associated with Skeletal-Related Event-Free or Overall Survival in Patients with Bone Metastases from Breast Cancer |
| title_full | Doxycycline-Induced Changes in Circulating MMP or TIMP2 Levels Are Not Associated with Skeletal-Related Event-Free or Overall Survival in Patients with Bone Metastases from Breast Cancer |
| title_fullStr | Doxycycline-Induced Changes in Circulating MMP or TIMP2 Levels Are Not Associated with Skeletal-Related Event-Free or Overall Survival in Patients with Bone Metastases from Breast Cancer |
| title_full_unstemmed | Doxycycline-Induced Changes in Circulating MMP or TIMP2 Levels Are Not Associated with Skeletal-Related Event-Free or Overall Survival in Patients with Bone Metastases from Breast Cancer |
| title_short | Doxycycline-Induced Changes in Circulating MMP or TIMP2 Levels Are Not Associated with Skeletal-Related Event-Free or Overall Survival in Patients with Bone Metastases from Breast Cancer |
| title_sort | doxycycline induced changes in circulating mmp or timp2 levels are not associated with skeletal related event free or overall survival in patients with bone metastases from breast cancer |
| topic | doxycycline breast cancer bone metastasis matrix metalloproteinase MMP2 MMP9 |
| url | https://www.mdpi.com/2072-6694/15/3/571 |
| work_keys_str_mv | AT huijunzhao doxycyclineinducedchangesincirculatingmmportimp2levelsarenotassociatedwithskeletalrelatedeventfreeoroverallsurvivalinpatientswithbonemetastasesfrombreastcancer AT gregorypond doxycyclineinducedchangesincirculatingmmportimp2levelsarenotassociatedwithskeletalrelatedeventfreeoroverallsurvivalinpatientswithbonemetastasesfrombreastcancer AT demetriossimos doxycyclineinducedchangesincirculatingmmportimp2levelsarenotassociatedwithskeletalrelatedeventfreeoroverallsurvivalinpatientswithbonemetastasesfrombreastcancer AT zhouwang doxycyclineinducedchangesincirculatingmmportimp2levelsarenotassociatedwithskeletalrelatedeventfreeoroverallsurvivalinpatientswithbonemetastasesfrombreastcancer AT susanrobertson doxycyclineinducedchangesincirculatingmmportimp2levelsarenotassociatedwithskeletalrelatedeventfreeoroverallsurvivalinpatientswithbonemetastasesfrombreastcancer AT gurmitsingh doxycyclineinducedchangesincirculatingmmportimp2levelsarenotassociatedwithskeletalrelatedeventfreeoroverallsurvivalinpatientswithbonemetastasesfrombreastcancer AT lisavandermeer doxycyclineinducedchangesincirculatingmmportimp2levelsarenotassociatedwithskeletalrelatedeventfreeoroverallsurvivalinpatientswithbonemetastasesfrombreastcancer AT markclemons doxycyclineinducedchangesincirculatingmmportimp2levelsarenotassociatedwithskeletalrelatedeventfreeoroverallsurvivalinpatientswithbonemetastasesfrombreastcancer AT christinalynnaddison doxycyclineinducedchangesincirculatingmmportimp2levelsarenotassociatedwithskeletalrelatedeventfreeoroverallsurvivalinpatientswithbonemetastasesfrombreastcancer |