- Email: [email protected]
Can iPCSK9-induced hypocholesterolemia starve cancer cells?
Accepted Manuscript Can iPCSK9-induced hypocholesterolemia starve cancer cells? Anne Gangloff, MD PhD, Frédéric Calon, PhD, Nabil G. Seidah, PhD PII:
S1933-2874(17)30135-6
DOI:
10.1016/j.jacl.2017.04.001
Reference:
JACL 1101
To appear in:
Journal of Clinical Lipidology
Received Date: 18 March 2017 Accepted Date: 4 April 2017
Please cite this article as: Gangloff A, Calon F, Seidah NG, Can iPCSK9-induced hypocholesterolemia starve cancer cells?, Journal of Clinical Lipidology (2017), doi: 10.1016/j.jacl.2017.04.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Can iPCSK9-induced hypocholesterolemia starve cancer cells? Anne Gangloff MD PhD
a,b
*, Frédéric Calon PhD c,d, Nabil G. Seidah PhD e
RI PT
Word count: 442 words
*Corresponding author
SC
Anne Gangloff MD PhD FRCPC Lipid Clinic, CHU de Québec
M AN U
2705 Laurier Boulevard Québec, QC, Canada G1V4G2 [email protected]
Clinic, CHU de Québec, Qc, Canada
b Endocrinology c Faculty
and nephrology research axis, CHU de Québec, Qc, Canada
EP
a Lipid
TE D
418-525-4444 ext.47275
of Pharmacy, Laval University, Québec, Qc, Canada research axis, CHU de Québec, Qc, Canada
AC C
d Neuroscience e Laboratory
of Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal, Qc,
Canada
Keywords: iPCSK9; cholesterol; cancer; incidence; progression; metastasis; evolocumab; alirocumab
Conflicts of interest: none
ACCEPTED MANUSCRIPT
Can iPCSK9-induced hypocholesterolemia starve cancer cells? a,b
*, Frédéric Calon PhD c,d, Nabil G. Seidah PhD e
RI PT
Anne Gangloff MD PhD
Cardiovascular disease (CVD) and cancer are the two leading causes of death in America1. LDLs not only promote atherosclerosis in a dose-dependent manner, they also provide
SC
cholesterol to peripheral cells, including cancer cells which have higher cholesterol requirements to sustain tumor growth. The availability of new classes of cholesterol-
M AN U
lowering drugs (CLDs) has pushed the frontiers of what is achievable in terms of cholesterol depletion. Indeed, the LAPLACE-22 and the FOURIER3 studies indicate that combining new monoclonal antibodies against PCSK9 (PCSK9i) with a statin can lower cholesterolemia much further than statins alone, with low density lipoprotein (LDL) levels as low as <25
TE D
mg/dL for more than 40% of individuals receiving high-intensity statin therapy2. Given our new ability to lower cholesterol to unprecedented levels, the following question is timely: can a combination of CLDs cause a cholesterol shortage so as to be used therapeutically to
EP
impair tumor growth and metastasis, especially for cancer subtypes relying on LDL uptake
AC C
for their cholesterol supply?
Cholesterol plays a key role in a plethora of cellular metabolic processes, particularly for highly demanding anabolic steps such as cell growth and division4. Cholesterol is an essential component of cellular membranes and lipid rafts, and is a precursor to all active steroids, including estrogens and androgens required for hormone-sensitive cancer
ACCEPTED MANUSCRIPT
proliferation4. Upregulation of the LDL receptor (LDLR) has been associated with cancer progression in LDLR positive cancers4,5,6.
RI PT
The strategy of slowing cancer progression by lowering circulating LDL cholesterol levels is supported by compelling data in animal models. Using PCSK9 knock-out mice, a model for hypocholesterolemia, it has been demonstrated that hypocholesterolemic animals had less
SC
melanoma metastasis in the liver than their normocholesterolemic counterparts7. However, feeding PCSK9-deficient hypocholesterolemic animals with a high cholesterol diet removed
M AN U
this protective effect, suggesting a cholesterol-mediated pathway7. In humans, Folsom et al reported that hypocholesterolemic individuals bearing loss-of-function mutations in PCSK9 were not at an increased risk of cancer, and if anything, tended to be protected from cancer8
TE D
(however, a lack of statistical power precluded a final confirmation of that point).
While a strong body of evidence indicates that cholesterol plays a role in cancer development, clinical confirmation that drug-induced hypocholesterolemia (LDL <25
EP
mg/dL) impairs tumorigenesis, cancer progression and metastasis is still lacking.
AC C
Therefore, the results from two large cardiovascular randomized control trials (RCTs) utilizing PCSK9 inhibitors on top of a statin (FOURIER3, ODYSSEY-OUTCOME9) are of particular interest.
Subgroup analysis of these trials comparing treatment-induced
hypocholesterolemic individuals to similar non-medicated individuals from the general population could provide first indications that CLD-induced hypocholesterolemia protects from cancer. If such observation is noted, trials designed to address the efficacy of druginduced hypocholesterolemia as an adjuvant treatment for cancers are warranted.
ACCEPTED MANUSCRIPT
Acknowledgment : self-funded
RI PT
Contributions : Anne Gangloff, Frédéric Calon and Nabil Seidah contributed to the scientific content, preparation and revision of the article.
Disclosure : All authors have approved the final version of the article.
SC
Conflicts of interest: none
M AN U
Reference List 1.
https://www.cdc.gov/nchs/fastats/leading-causes-of-death.htm
2.
Robinson JG, Nedergaard BS, Rogers WJ, Fialkow J, Neutel JM, Ramstad D, et al. Effect
of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C
TE D
lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. Jama. 2014;311(18):1870-82. Epub 2014/05/16. 3.
Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al.
EP
Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. The New England journal of medicine. Epub March 17, 2017. Cruz PM, Mo H, McConathy WJ, Sabnis N, Lacko AG. The role of cholesterol
AC C
4.
metabolism and cholesterol transport in carcinogenesis: a review of scientific findings, relevant to future cancer therapeutics. Frontiers in pharmacology. 2013;4:119. Epub 2013/10/05. 5.
Vasseur S, Guillaumond F. LDL Receptor: An open route to feed pancreatic tumor
cells. Molecular & Cellular Oncology. 2016;3(1):e1033586. doi:10.1080/23723556.2015.1033586.
ACCEPTED MANUSCRIPT
6.
Guillaumond F, Bidaut G, Ouaissi M, Servais S, Gouirand V, Olivares O, et al.
Cholesterol uptake disruption, in association with chemotherapy, is a promising combined metabolic therapy for pancreatic adenocarcinoma. Proceedings of the National Academy of
7.
RI PT
Sciences of the United States of America. 2015;112(8):2473-8. Epub 2015/02/13.
Sun X, Essalmani R, Day R, Khatib AM, Seidah NG, Prat A. Proprotein convertase
2012;14(12):1122-31. Epub 2013/01/12. 8.
SC
subtilisin/kexin type 9 deficiency reduces melanoma metastasis in liver. Neoplasia.
Folsom AR, Peacock JM, Boerwinkle E. Sequence variation in proprotein convertase
M AN U
subtilisin/kexin type 9 serine protease gene, low LDL cholesterol, and cancer incidence. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2007;16(11):2455-8. Epub 2007/11/17.
Schwartz GG, Bessac L, Berdan LG, Bhatt DL, Bittner V, Diaz R et al. Effect of
TE D
9.
alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: Rationale and design of the ODYSSEY Outcomes trial.
AC C
EP
American Heart Journal. 2014. Volume 168 , Issue 5 , 682 - 689.e1
ACCEPTED MANUSCRIPT
Highlights
EP
TE D
M AN U
SC
RI PT
LDLs provide cholesterol to peripheral cells, including cancer cells Cancer cells have higher cholesterol requirements to sustain tumor growth LDL <25 mg/dL have been reported with PCSK9 inhibitors on top of a statin A combination of cholesterol lowering drugs (CLDs) could find use in cancer therapy Clinical validation that CLDs slow cancer progression and metastasis is required
AC C
• • • • •
S1933-2874(17)30135-6
DOI:
10.1016/j.jacl.2017.04.001
Reference:
JACL 1101
To appear in:
Journal of Clinical Lipidology
Received Date: 18 March 2017 Accepted Date: 4 April 2017
Please cite this article as: Gangloff A, Calon F, Seidah NG, Can iPCSK9-induced hypocholesterolemia starve cancer cells?, Journal of Clinical Lipidology (2017), doi: 10.1016/j.jacl.2017.04.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Can iPCSK9-induced hypocholesterolemia starve cancer cells? Anne Gangloff MD PhD
a,b
*, Frédéric Calon PhD c,d, Nabil G. Seidah PhD e
RI PT
Word count: 442 words
*Corresponding author
SC
Anne Gangloff MD PhD FRCPC Lipid Clinic, CHU de Québec
M AN U
2705 Laurier Boulevard Québec, QC, Canada G1V4G2 [email protected]
Clinic, CHU de Québec, Qc, Canada
b Endocrinology c Faculty
and nephrology research axis, CHU de Québec, Qc, Canada
EP
a Lipid
TE D
418-525-4444 ext.47275
of Pharmacy, Laval University, Québec, Qc, Canada research axis, CHU de Québec, Qc, Canada
AC C
d Neuroscience e Laboratory
of Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal, Qc,
Canada
Keywords: iPCSK9; cholesterol; cancer; incidence; progression; metastasis; evolocumab; alirocumab
Conflicts of interest: none
ACCEPTED MANUSCRIPT
Can iPCSK9-induced hypocholesterolemia starve cancer cells? a,b
*, Frédéric Calon PhD c,d, Nabil G. Seidah PhD e
RI PT
Anne Gangloff MD PhD
Cardiovascular disease (CVD) and cancer are the two leading causes of death in America1. LDLs not only promote atherosclerosis in a dose-dependent manner, they also provide
SC
cholesterol to peripheral cells, including cancer cells which have higher cholesterol requirements to sustain tumor growth. The availability of new classes of cholesterol-
M AN U
lowering drugs (CLDs) has pushed the frontiers of what is achievable in terms of cholesterol depletion. Indeed, the LAPLACE-22 and the FOURIER3 studies indicate that combining new monoclonal antibodies against PCSK9 (PCSK9i) with a statin can lower cholesterolemia much further than statins alone, with low density lipoprotein (LDL) levels as low as <25
TE D
mg/dL for more than 40% of individuals receiving high-intensity statin therapy2. Given our new ability to lower cholesterol to unprecedented levels, the following question is timely: can a combination of CLDs cause a cholesterol shortage so as to be used therapeutically to
EP
impair tumor growth and metastasis, especially for cancer subtypes relying on LDL uptake
AC C
for their cholesterol supply?
Cholesterol plays a key role in a plethora of cellular metabolic processes, particularly for highly demanding anabolic steps such as cell growth and division4. Cholesterol is an essential component of cellular membranes and lipid rafts, and is a precursor to all active steroids, including estrogens and androgens required for hormone-sensitive cancer
ACCEPTED MANUSCRIPT
proliferation4. Upregulation of the LDL receptor (LDLR) has been associated with cancer progression in LDLR positive cancers4,5,6.
RI PT
The strategy of slowing cancer progression by lowering circulating LDL cholesterol levels is supported by compelling data in animal models. Using PCSK9 knock-out mice, a model for hypocholesterolemia, it has been demonstrated that hypocholesterolemic animals had less
SC
melanoma metastasis in the liver than their normocholesterolemic counterparts7. However, feeding PCSK9-deficient hypocholesterolemic animals with a high cholesterol diet removed
M AN U
this protective effect, suggesting a cholesterol-mediated pathway7. In humans, Folsom et al reported that hypocholesterolemic individuals bearing loss-of-function mutations in PCSK9 were not at an increased risk of cancer, and if anything, tended to be protected from cancer8
TE D
(however, a lack of statistical power precluded a final confirmation of that point).
While a strong body of evidence indicates that cholesterol plays a role in cancer development, clinical confirmation that drug-induced hypocholesterolemia (LDL <25
EP
mg/dL) impairs tumorigenesis, cancer progression and metastasis is still lacking.
AC C
Therefore, the results from two large cardiovascular randomized control trials (RCTs) utilizing PCSK9 inhibitors on top of a statin (FOURIER3, ODYSSEY-OUTCOME9) are of particular interest.
Subgroup analysis of these trials comparing treatment-induced
hypocholesterolemic individuals to similar non-medicated individuals from the general population could provide first indications that CLD-induced hypocholesterolemia protects from cancer. If such observation is noted, trials designed to address the efficacy of druginduced hypocholesterolemia as an adjuvant treatment for cancers are warranted.
ACCEPTED MANUSCRIPT
Acknowledgment : self-funded
RI PT
Contributions : Anne Gangloff, Frédéric Calon and Nabil Seidah contributed to the scientific content, preparation and revision of the article.
Disclosure : All authors have approved the final version of the article.
SC
Conflicts of interest: none
M AN U
Reference List 1.
https://www.cdc.gov/nchs/fastats/leading-causes-of-death.htm
2.
Robinson JG, Nedergaard BS, Rogers WJ, Fialkow J, Neutel JM, Ramstad D, et al. Effect
of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C
TE D
lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. Jama. 2014;311(18):1870-82. Epub 2014/05/16. 3.
Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al.
EP
Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. The New England journal of medicine. Epub March 17, 2017. Cruz PM, Mo H, McConathy WJ, Sabnis N, Lacko AG. The role of cholesterol
AC C
4.
metabolism and cholesterol transport in carcinogenesis: a review of scientific findings, relevant to future cancer therapeutics. Frontiers in pharmacology. 2013;4:119. Epub 2013/10/05. 5.
Vasseur S, Guillaumond F. LDL Receptor: An open route to feed pancreatic tumor
cells. Molecular & Cellular Oncology. 2016;3(1):e1033586. doi:10.1080/23723556.2015.1033586.
ACCEPTED MANUSCRIPT
6.
Guillaumond F, Bidaut G, Ouaissi M, Servais S, Gouirand V, Olivares O, et al.
Cholesterol uptake disruption, in association with chemotherapy, is a promising combined metabolic therapy for pancreatic adenocarcinoma. Proceedings of the National Academy of
7.
RI PT
Sciences of the United States of America. 2015;112(8):2473-8. Epub 2015/02/13.
Sun X, Essalmani R, Day R, Khatib AM, Seidah NG, Prat A. Proprotein convertase
2012;14(12):1122-31. Epub 2013/01/12. 8.
SC
subtilisin/kexin type 9 deficiency reduces melanoma metastasis in liver. Neoplasia.
Folsom AR, Peacock JM, Boerwinkle E. Sequence variation in proprotein convertase
M AN U
subtilisin/kexin type 9 serine protease gene, low LDL cholesterol, and cancer incidence. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2007;16(11):2455-8. Epub 2007/11/17.
Schwartz GG, Bessac L, Berdan LG, Bhatt DL, Bittner V, Diaz R et al. Effect of
TE D
9.
alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: Rationale and design of the ODYSSEY Outcomes trial.
AC C
EP
American Heart Journal. 2014. Volume 168 , Issue 5 , 682 - 689.e1
ACCEPTED MANUSCRIPT
Highlights
EP
TE D
M AN U
SC
RI PT
LDLs provide cholesterol to peripheral cells, including cancer cells Cancer cells have higher cholesterol requirements to sustain tumor growth LDL <25 mg/dL have been reported with PCSK9 inhibitors on top of a statin A combination of cholesterol lowering drugs (CLDs) could find use in cancer therapy Clinical validation that CLDs slow cancer progression and metastasis is required
AC C
• • • • •