Amlodipine with letrozole as maintenance post chemotherapy –targeting calcium calcinuerin calmodulin pathway and aromatase inhibitor indisseminated Endometrioid adenocarcinoma of the endometrium a – A case report

Amlodipine with letrozole as maintenance post chemotherapy –targeting calcium calcinuerin calmodulin pathway and aromatase inhibitor indisseminated Endometrioid adenocarcinoma of the endometrium a – A case report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Amlodipine with letrozole as maintenance post chemotherapy –targeting calcium calcinuerin calmodulin pathway and aromatase inhibitor indisseminated Endometrioid adenocarcinoma of the endometrium a – A case report Mukul Arvind Gharote, Amruta Ashok Deshpande, Amogh Satchitanand Kale This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6410162/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: World is now clinging to immune checkpoint inhibitor in almost every type of cancer. PD-1 and PD-L1 inhibitor are taking over the treatment algorithm. But cost is an issue; we have a perspective to target energy mechanism of cytotoxic T cells to modulate the representation of PD-1 receptor so as to increase immunogenicity of cytotoxic T cells. Cellular energy mechanism is largely dependent on calcium channels and pharmacological modulation of it may help in modulating response of cytotoxicT cell. Clinical case; We hereby present a case of endometroid adenocarcinoma of endometrium successfully treated with CCB and hormonal treatment after a short course of chemotherapy. (paclitaxel 80 mg/m2 weekly and carboplatin AUC-2) given on weekly basis, she is still in remission, to begin with she was a case of stage IV ca endometrium due to peritoneal seeding of the disease( TNM& FIGO) , but gradually her stage reversed back to stage 1 ( TNM) and after hysterectomy is now disease free since last 3 years. Conclusion: This case study hints at possible role of Calcium channel blockers (CCB) and Calcium modulation, which plays a pivotal role in the energy mechanism of cytotoxic T cells. 1 Modulation of Calcium influx can modify the T cell activation and proliferation 1 .Estrogen plays critical role in the upregulation of calcium related proteins. Calcium channel blockers(CCB) likeamlodipine, hence can be considered for repurposingin thetreatment of endometrial cancer. 2 Amlodipine a CCB can be used along with letrozole especially in female reproductive tract malignancies like endometrial malignancies are concerned. Oncology Internal Medicine Amlodipine Endometroid adenocarcinoma of endometrium calcium channel blockers ( CCB) PD-1 receptor Figures Figure 1 Figure 2 Introduction Amlodipine is hypothesised to have additive role in combination with hormonal therapy in the treatment of advanced endometrial cancer 2 but we didn’t have a clinical use of this combination, our case report helps and encourages for further research of its use in endometrial cancer.We hope that this case serves as a beacon to guide further research in this regard.Methods: This is retrospective observational case report; hence ethics review board permission was not taken, Case history: A 77-year-old female was admitted for postmenopausal bleeding,on examination her Per speculum examination was suggestive of minimal altered coloured due to bleeding. Her lab investigation was CA 125 of 91.7IU/ml. MRI abdomen and pelvis was suggestive of 27*25*62 mm lesion in endometrial cavity with intralesional haemorrhagic areas. She underwent endometrial biopsy suggestive of epithelial malignancy. She was hypertensive and was taking Amlodipine 5 mg with atenolol 80 mg as concomitant medication., The cause of her hypertension was primary hypertension.She was posted for laparotomy but intraoperative finding was s/o omental seeding with metastasis on serosal aspect of uterus, fallopian tube and ovaries, omental biopsy was taken which was suggestive of endometrial carcinoma. Her biopsy sample was further investigated with Immunohistochemistry suggestive of estrogen(90%) and progesterone receptor (70%) positive, tumour cells were expressing pax-8 & p53- wild type. Her sanger sequencing was suggestive of POLE-1, (Sanger sequencing and exon screened were exon 9,10,11,12,13,14) and TP-53 wild type and mismatch repair gene deficient. (MMR-D) with loss of nuclear expression of MLH-1 and PMS-2.Her PET scan done on 07/01/21 was suggestive of left adnexal lesion and FDG avid lesionendometrial lesion of size 2.1*2.4*3.2 cm, specific uptake value (SUV-16.19)along with omental and peritoneal lesionwith FDG avid retroperitonealand iliac lymphadenopathy(SUV 12.02) as shown in figure 1. Figure -1 She was reluctant for chemotherapy, after explaining her about the risk: benefit of short course chemotherapy, hence a short course of weekly paclitaxel (80 mg/m2) + carboplatin (AUC-2) for 12 weeks followed by hormonal treatment. Short course was planned in accordance to data published by Secord AA et al 2007 and vandeput I et al 3,4 .Post 12 weeks of chemotherapy CT scan abdomen and pelvis was suggestive of reduction in her primary with no evidence of abdominal lymphadenopathy. She was reluctant to undergo surgery at that time and hence for 2 years she maintained her regimen, after 2 years she had an episode of per vaginum bleeding hence PET scan was done at the end of 2 years of hormonal and amlodipine treatment on 22/08/2023 which was suggestive of minimal increase in size with no change in metabolic activity of the primary now measuring 2.4*2.6*3.5 cm.(SUV-15.95). Surprisingly her left adnexal lesion was completely resolved, besides all her omental and peritoneal thickening were completely resolved. While all the retroperitoneal nodes and iliac nodes were significantly reduced and were rendered ametabolic. She underwent radical hysterectomy with retroperitoneal lymph node dissection on 25/08/23. Her histopathology report was suggestive of High-grade serous carcinoma of endometrium - TNM pathological stage - ypT1aN0,Tumourwas confined to endometrial cavity with no invasion in uterine wall as shown in figure -2.Fallopian tubes, ovaries, lymph nodes,omentumwere free from tumour invasion/metastasis. Her pelvic lymph node dissection did not reveal any tumour metastasis even microscopically. Figure -2 She is still in remission and is taking her hormonal tablets of letrozole 5 mg along with amlodipine 5 mg. Discussion PI3K/AKT/mTOR pathway which is regulated by PTEN is the pathway commonly altered inestrogen derived endometrial cancer 5 . There is extremely close link between ca2+ and PI3K/AKT signalling in endothelial cells, although the isoforms of PI3K are not well-known 6 .This signalling is crucial to control angiogenesis. 6 Calcium channel blockers( CCB) like amlodipine can suppress phosphorylation of ERK/PI3K in neutrophils , induced by proinflammatory cytokines like TNF-α. 7 Calcium channel blocker like nifedipine effectively suppress the fast calcium inflow in endometrial cancer cells caused by estrogen. 8 Additionally inhibition of T type voltage gated calcium channel has been found to decreasehec 1 cells, invitro cell line of a human endometrial adenocarcinoma. 9 Both T type or L type calcium channel blockers can be repurposed for the treatment of endometrial adenocarcinoma. 2,10 L type CCB regulate filopodia stability and is relevant as anticancer , not only in breast cancer but also in p53 mutated other cancers as well. Our case of endometrial cancer is p53 mutated. 11 Calcium plays important role in lymphocyte activation and maturation 1 ,it also plays a central stage in genetic modulation especially of transcription factor NFAT-2. 12 calcineurin kinase negatively regulates activation of NFAT kinases and hence opposes NFAT activation, thus calcium channel blocker or calcineurin inhibitors like cyclosporin can effectively activate NFAT. This activation of NFAT-2 promotes its translocation to nuclear domain and resultant T cell activation and response. Impaired dephosphorylation and nuclear translocation of NFAT results in immunodeficiency. 13 Letrozole alone cannot be attributed for the complete remission achieved in our case, as endometrial cancer is known to harbour PI3K which leads to resistance 4,14 . Overall letrozole alone is having a modest activity in endometrial cancer 15 . Considering it as causal relation for the treatment result in our case would be to ignore the proven benefits of CCB’s on PI3K pathway. Now coming up to female reproductive tract malignancies especially in endometrial carcinoma,CCB have important role in disruption oftumour microenvironment. 2 Amlodipine can augment immunotherapy effects by depleting PD-L1 expression 16 . In the treatment of endometrial cancer, especially in hormone sensitive endometrial cancer we report prescribing Amlodipine in hypertensive patient can help in the treatment armamentarium. It may be considered as the world’s most economical immune checkpoint inhibitor if we have a large-scale trial using it. In our case of endometrial cancer, we report use of amlodipine along with conventional medicines and hormonal therapy has additional benefits in treatment outcome especially if the patient is hypertensive. We waited for 4 years to see for the endurance of its use and at the time of writing of this case report, patient is still hale and hearty. We have her latest USG abdomen + pelvis done to consolidate our finding. As per NCCN criteria version 3.2025,surveillance is based on clinical examination, her clinical examination done regularly doesn’t show any evidence of vault recurrence. based on these findingswe can safely conclude that she is still disease free. Thus,this case exceeds the median trial outcomes making it one of the notable cases altogether albeit with speculative role of amlodipine but is certainly introduces a novel angle for future research in this area. Limitation of this case study is that its difficult to prove the role of amlodipine in endometrial cancer based on single case study, further research is validated. Key tekaways would be that if the hypertensive patient is on amlodipine , kindly do not change unless her hypertension is worsening as there is albeit speculative role of amlodipine in endometrial cancer. Declarations The patient herself consented to publish the case report. Funding declaration : No funding References Feske S, Giltnane J, Dolmetsch R, Staudt LM, Rao A (2001) Gene regulation mediated by calcium signals in T lymphocytes. Nat Immunol. ;2(4):316 – 24. doi: 10.1038/86318. Erratum in: Nat Immunol. 2008;9(3):328-9. PMID: 11276202 Huang T, Zhou J, Wang J (2022) Calcium and calcium-related proteins in endometrial cancer: opportunities for pharmacological intervention. Int J Biol Sci 18(3):1065–1078. 10.7150/ijbs.68591 PMID: 35173539; PMCID: PMC8771838 Secord AA, Havrilesky LJ, Carney ME, Soper JT, Clarke-Pearson DL, Rodriguez GC, Berchuck A (2007) Weekly low-dose paclitaxel and carboplatin in the treatment of advanced or recurrent cervical and endometrial cancer. Int J Clin Oncol 12(1):31–36. 10.1007/s10147-006-0619-9 Epub 2007 Feb 25. PMID: 17380438 Vandenput I, Vergote I, Neven P, Amant F (2012) Weekly paclitaxel-carboplatin regimen in patients with primary advanced or recurrent endometrial carcinoma. Int J Gynecol Cancer. ;22(4):617 – 22. 10.1097/IGC.0b013e31824a3385 . PMID: 22426408 Yeramian A, Moreno-Bueno G, Dolcet X, Catasus L, Abal M, Colas E, Reventos J et al (2013) Endometrial carcinoma: molecular alterations involved in tumor development and progression. Oncogene 32(4):403–413. 10.1038/onc.2012.76 Epub 2012 Mar 19. PMID: 22430211 Ghigo A, Laffargue M, Li M, Hirsch E (2017) PI3K and Calcium Signaling in Cardiovascular Disease. Circ Res. ;121(3):282–292. 10.1161/CIRCRESAHA.117.310183 . PMID: 28729453 Shima E, Katsube M, Kato T, Kitagawa M, Hato F, Hino M et al (2008) Calcium channel blockers suppress cytokine-induced activation of human neutrophils. Am J Hypertens. ;21(1):78–84. 10.1038/ajh.2007.13 . PMID: 18091748 Hunek G, Zembala J, Januszewski J, Bełżek A, Syty K, Jabiry-ZieniewiczZ et al (2024) Micro- and Macronutrients in Endometrial Cancer-From Metallomic Analysis to Improvements in Treatment Strategies. Int J Mol Sci 25(18):9918. 10.3390/ijms25189918 PMID: 39337406; PMCID: PMC11432114 Bao XX, Wang JL, Wei LH (2012) Impact of calcium channel antagonists for estrogen action on the endometrial carcinoma HEC-1A cells. Zhonghua fu chan ke za zhi 47(3):212–217 Huang T, Zhou J, Zhang L, Yang X, Cheng Y, Yin S et al Azelnidipine nanoparticles break calcium homeostasis and induce severe ER stress combined with medroxyprogesterone acetate for endometrial cancer therapy,NanoToday,47,2022,101682,ISSN 1748 – 0132, https://doi.org/10.1016/j.nantod.2022.101682 Jacquemet G, Baghirov H, Georgiadou M et al (2016) L-type calcium channels regulate filopodia stability and cancer cell invasion downstream of integrin signalling. Nat Commun 7:13297. https://doi.org/10.1038/ncomms13297 Gharote MA (2021) Amlodipine-induced inhibition of NFAT-2 nuclear translocation and its utility as an additive to immune checkpoint inhibitor. Int J Mol Immuno Oncol 6(3):145–148 Feske S, Draeger R, Peter HH, Rao A (2000) Impaired NFAT regulation and its role in a severe combined immunodeficiency. Immunobiology. ;202(2):134 – 50. 10.1016/S0171-2985(00)80060-1 . PMID: 10993288 Slomovitz BM, Jiang Y, Yates MS, Soliman PT, Johnston T, Nowakowski M et al (2015) Phase II study of everolimus and letrozole in patients with recurrent endometrial carcinoma. J Clin Oncol 33(8):930–936. 10.1200/JCO.2014.58.3401 Epub 2015 Jan 26. PMID: 25624430; PMCID: PMC4348638 Wagner VM, Backes FJ (2023) Do Not Forget about Hormonal Therapy for Recurrent Endometrial Cancer: A Review of Options, Updates, and New Combinations. Cancers (Basel) 15(6):1799. 10.3390/cancers15061799 PMID: 36980685; PMCID: PMC10046539 Li C, Yao H, Wang H, Fang JY, Xu J (2021) Repurposing screen identifies Amlodipine as an inducer of PD-L1 degradation and antitumor immunity. Oncogene 40(6):1128–1146. 10.1038/s41388-020-01592-6 Epub 2020 Dec 15. PMID: 33323966 Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6410162","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":440523289,"identity":"11d8dad5-b4eb-489e-bbd5-4cddd472c388","order_by":0,"name":"Mukul Arvind Gharote","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6UlEQVRIie3PMQrCMBSA4RcKnRRXLyHoIt7FpUGIU1xcOtQSEeriASpKvYJdOlcK6RJ0FVw6OevWRTA16CK2ujnkh8AL5CMJgE73l5kAGYClNrZchsGqiaUIYiAKgn4hyANFy2r5hDQtmIwaqyTNrsGk35hLktvRR9I9Ei5JOm7uCZ4uo5T6ibxtIU4lZOhJwjETtc6sHnHKJDGQ9wXZFOS25nRTTR4Pc/C2IIg5dFtJxHnQs9oxDoWJlwse01CSXelfUtI5XmwXB8KIL7nj0uCQ7LLc/kxU7eQ5qSGuOF/kvg06nU6ne3UHuCVihhLYTEYAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-3302-3204","institution":"Mukta Cancer Clinic, Nashik","correspondingAuthor":true,"prefix":"","firstName":"Mukul","middleName":"Arvind","lastName":"Gharote","suffix":""},{"id":440524329,"identity":"9494739a-9b3e-455e-8bb3-2dd182b58ba6","order_by":1,"name":"Amruta Ashok Deshpande","email":"","orcid":"","institution":"Mukta Cancer Clinic, Nashik","correspondingAuthor":false,"prefix":"","firstName":"Amruta","middleName":"Ashok","lastName":"Deshpande","suffix":""},{"id":440524330,"identity":"afa7b8e1-46d3-492b-bfa2-e3a6b5c4eb2a","order_by":2,"name":"Amogh Satchitanand Kale","email":"","orcid":"","institution":"Mukta Cancer Clinic, Nashik","correspondingAuthor":false,"prefix":"","firstName":"Amogh","middleName":"Satchitanand","lastName":"Kale","suffix":""}],"badges":[],"createdAt":"2025-04-09 09:10:45","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":true,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-6410162/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6410162/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":80833154,"identity":"3fc8eac3-5612-45f8-938e-0c54388fbd6a","added_by":"auto","created_at":"2025-04-17 14:23:58","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":265437,"visible":true,"origin":"","legend":"\u003cp\u003eSuggestive of peritoneal and pelvic Lymph node along with adnexal mass.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6410162/v1/da6b10129a6a44e0048857b6.png"},{"id":80833148,"identity":"5b8b4cb2-8120-4841-9e69-bec6844d8af0","added_by":"auto","created_at":"2025-04-17 14:23:56","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":366201,"visible":true,"origin":"","legend":"\u003cp\u003eGrossing and microscopy\u003c/p\u003e\n\u003cp\u003eShowing gross features of hysterectomy sample,tumour is seen confined to the endometrial cavity,adenexa is free of tumour.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6410162/v1/446ac823fb192563a6263992.png"},{"id":80833731,"identity":"83713591-bd33-4a12-8eb2-a38c3fa2a4c1","added_by":"auto","created_at":"2025-04-17 14:32:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1097726,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6410162/v1/8e4999d6-27c4-40fd-a014-5077d9e4e184.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eAmlodipine with letrozole as maintenance post chemotherapy –targeting calcium calcinuerin calmodulin pathway and aromatase inhibitor indisseminated Endometrioid adenocarcinoma of the endometrium a – A case report\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAmlodipine is hypothesised to have additive role in combination with hormonal therapy in the treatment of advanced endometrial cancer \u003csup\u003e2\u003c/sup\u003e but we didn\u0026rsquo;t have a clinical use of this combination, our case report helps and encourages for further research of its use in endometrial cancer.We hope that this case serves as a beacon to guide further research in this regard.Methods: This is retrospective observational case report; hence ethics review board permission was not taken, Case\u003cstrong\u003ehistory:\u003c/strong\u003eA 77-year-old female was admitted for postmenopausal bleeding,on examination her Per speculum examination was suggestive of minimal altered coloured due to bleeding. Her lab investigation was CA 125 of 91.7IU/ml. MRI abdomen and pelvis was suggestive of 27*25*62 mm lesion in endometrial cavity with intralesional haemorrhagic areas. She underwent endometrial biopsy suggestive of epithelial malignancy. \u0026nbsp;She was hypertensive and was taking Amlodipine 5 mg with atenolol 80 mg as concomitant medication., The cause of her hypertension was primary hypertension.She was posted for laparotomy but intraoperative finding was s/o omental seeding with metastasis on serosal aspect of uterus, fallopian tube and ovaries, omental biopsy was taken which was suggestive of endometrial carcinoma. Her biopsy sample was further investigated with Immunohistochemistry suggestive of estrogen(90%) and progesterone receptor (70%) positive, tumour cells were expressing pax-8 \u0026amp; p53- wild type. Her sanger sequencing was suggestive of POLE-1, (Sanger sequencing and exon screened were exon 9,10,11,12,13,14) and TP-53 wild type and mismatch repair gene deficient. (MMR-D) with loss of nuclear expression of MLH-1 and PMS-2.Her PET scan done on 07/01/21 was suggestive of left adnexal lesion and FDG avid lesionendometrial lesion of size 2.1*2.4*3.2 cm, specific uptake value (SUV-16.19)along with omental and peritoneal lesionwith FDG avid retroperitonealand iliac lymphadenopathy(SUV 12.02) as shown in figure 1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFigure -1\u003c/p\u003e\n\u003cp\u003eShe was reluctant for chemotherapy, after explaining her about the risk: benefit of short course chemotherapy, hence a short course of weekly paclitaxel (80 mg/m2) + carboplatin (AUC-2) for 12 weeks followed by hormonal treatment. Short course was planned in accordance to data published by Secord AA et al 2007 and vandeput I et al\u003csup\u003e3,4\u003c/sup\u003e.Post 12 weeks of chemotherapy CT scan abdomen and pelvis was suggestive of reduction in her primary with no evidence of abdominal lymphadenopathy. She was reluctant to undergo surgery at that time and hence for 2 years she maintained her regimen, after 2 years she had an episode of per vaginum bleeding hence PET scan was done at the end of 2 years of hormonal and amlodipine treatment on 22/08/2023 which was suggestive of minimal increase in size with no change in metabolic activity of the primary now measuring 2.4*2.6*3.5 cm.(SUV-15.95). Surprisingly her left adnexal lesion was completely resolved, besides all her omental and peritoneal thickening were completely resolved. While all the retroperitoneal nodes and iliac nodes were significantly reduced and were rendered ametabolic.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eShe underwent radical hysterectomy with retroperitoneal lymph node dissection on 25/08/23. Her histopathology report was suggestive of High-grade serous carcinoma of endometrium - TNM pathological stage - ypT1aN0,Tumourwas confined to endometrial cavity with no invasion in uterine wall as shown in figure -2.Fallopian tubes, ovaries, lymph nodes,omentumwere free from tumour invasion/metastasis. Her pelvic lymph node dissection did not reveal any tumour metastasis even microscopically.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFigure -2\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eShe is still in remission and is taking her hormonal tablets of letrozole 5 mg along with amlodipine 5 mg.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003ePI3K/AKT/mTOR pathway which is regulated by PTEN is the pathway commonly altered inestrogen derived endometrial cancer\u003csup\u003e5\u003c/sup\u003e. There is extremely close link between ca2+ and PI3K/AKT signalling in endothelial cells, although the isoforms of PI3K are not well-known\u003csup\u003e6\u003c/sup\u003e.This signalling is crucial to control angiogenesis.\u003csup\u003e6\u003c/sup\u003eCalcium channel blockers( CCB) like amlodipine can suppress phosphorylation of ERK/PI3K in neutrophils , induced by proinflammatory cytokines like TNF-\u0026alpha;.\u003csup\u003e7\u003c/sup\u003eCalcium channel blocker like nifedipine effectively suppress the fast calcium inflow in endometrial cancer cells caused by estrogen.\u003csup\u003e8\u003c/sup\u003eAdditionally inhibition of T type voltage gated calcium channel has been found to decreasehec 1 cells, invitro cell line of a human endometrial adenocarcinoma.\u003csup\u003e9\u003c/sup\u003eBoth T type or L type calcium channel blockers can be repurposed for the treatment of endometrial adenocarcinoma.\u003csup\u003e2,10\u003c/sup\u003e L type CCB regulate filopodia stability and is relevant as anticancer , not only in breast cancer but also in p53 mutated other cancers as well. Our case of endometrial cancer is p53 mutated.\u003csup\u003e11\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eCalcium plays important role in lymphocyte activation and maturation\u003csup\u003e1\u003c/sup\u003e,it also plays a central stage in genetic modulation especially of transcription factor NFAT-2.\u003csup\u003e12\u003c/sup\u003ecalcineurin kinase negatively regulates activation of NFAT kinases and hence opposes NFAT activation, thus calcium channel blocker or calcineurin inhibitors like cyclosporin can effectively activate NFAT. This activation of NFAT-2 promotes its translocation to nuclear domain and resultant T cell activation and response. Impaired dephosphorylation and nuclear translocation of NFAT results in immunodeficiency.\u003csup\u003e13\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eLetrozole alone cannot be attributed for the complete remission achieved in our case, as endometrial cancer is known to harbour PI3K which leads to resistance \u003csup\u003e4,14\u003c/sup\u003e. Overall letrozole alone is having a modest activity in endometrial cancer\u003csup\u003e15\u003c/sup\u003e. Considering it as causal relation for the treatment result in our case would be to ignore the proven benefits of CCB\u0026rsquo;s on PI3K pathway.\u003c/p\u003e\n\u003cp\u003eNow coming up to female reproductive tract malignancies especially in endometrial carcinoma,CCB have important role in disruption oftumour microenvironment.\u003csup\u003e2\u003c/sup\u003eAmlodipine can augment immunotherapy effects by depleting PD-L1 expression\u003csup\u003e16\u003c/sup\u003e. In the treatment of endometrial cancer, especially in hormone sensitive endometrial cancer we report prescribing Amlodipine in hypertensive patient can help in the treatment armamentarium. It may be considered as the world\u0026rsquo;s most economical immune checkpoint inhibitor if we have a large-scale trial using it.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn our case of endometrial cancer, we report use of amlodipine along with conventional medicines and hormonal therapy has additional benefits in treatment outcome especially if the patient is hypertensive.\u003c/p\u003e\n\u003cp\u003eWe waited for 4 years to see for the endurance of its use and at the time of writing of this case report, patient is still hale and hearty. We have her latest USG abdomen + pelvis done to consolidate our finding. As per NCCN criteria version 3.2025,surveillance is based on clinical examination, her clinical examination done regularly doesn\u0026rsquo;t show any evidence of vault recurrence. based on these findingswe can safely conclude that she is still disease free. Thus,this case exceeds the median trial outcomes making it one of the notable cases altogether albeit with speculative role of amlodipine but is certainly \u0026nbsp;introduces a novel angle for future research in this area.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLimitation of this case study is that its difficult to prove the role of amlodipine in endometrial cancer based on single case study, further research is validated. Key tekaways would be that if the hypertensive patient is on amlodipine , kindly do not change unless her hypertension is worsening as there is albeit speculative role of amlodipine in endometrial cancer.\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cspan\u003eThe patient herself consented to publish the case report.\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan\u003eFunding declaration : No funding\u0026nbsp;\u003c/span\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eFeske S, Giltnane J, Dolmetsch R, Staudt LM, Rao A (2001) Gene regulation mediated by calcium signals in T lymphocytes. Nat Immunol. ;2(4):316\u0026thinsp;\u0026ndash;\u0026thinsp;24. doi: 10.1038/86318. Erratum in: Nat Immunol. 2008;9(3):328-9. 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PMID: 33323966\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Mukta Cancer Clinic, nashik. mahrashtra.","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Amlodipine,Endometroid adenocarcinoma of endometrium, calcium channel blockers ( CCB), PD-1 receptor","lastPublishedDoi":"10.21203/rs.3.rs-6410162/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6410162/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: World is now clinging to immune checkpoint inhibitor in almost every type of cancer. PD-1 and PD-L1 inhibitor are taking over the treatment algorithm. But cost is an issue; we have a perspective to target energy mechanism of cytotoxic T cells to modulate the representation of PD-1 receptor so as to increase immunogenicity of cytotoxic T cells. Cellular energy mechanism is largely dependent on calcium channels and pharmacological modulation of it may help in modulating response of cytotoxicT cell. Clinical case; We hereby present a case of endometroid adenocarcinoma of endometrium successfully treated with CCB and hormonal treatment after a short course of chemotherapy. (paclitaxel 80 mg/m2 weekly and carboplatin AUC-2) given on weekly basis, she is still in remission, to begin with she was a case of stage IV ca endometrium due to peritoneal seeding of the disease( TNM\u0026amp; FIGO) , but gradually her stage reversed back to stage 1 ( TNM) \u0026nbsp;and after hysterectomy is now disease free since last 3 years.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConclusion: This case study hints at possible role of Calcium channel blockers (CCB) and Calcium modulation, which plays a pivotal role in the energy mechanism of cytotoxic T cells.\u003csup\u003e1\u003c/sup\u003eModulation of Calcium influx can modify the T cell activation and proliferation \u003csup\u003e1\u003c/sup\u003e.Estrogen plays critical role in the upregulation of calcium related proteins. Calcium channel blockers(CCB) likeamlodipine, hence can be considered for repurposingin thetreatment of endometrial cancer.\u003csup\u003e2 \u003c/sup\u003eAmlodipine a CCB can be used along with letrozole especially in female reproductive tract malignancies like endometrial malignancies are concerned.\u003c/p\u003e","manuscriptTitle":"Amlodipine with letrozole as maintenance post chemotherapy –targeting calcium calcinuerin calmodulin pathway and aromatase inhibitor indisseminated Endometrioid adenocarcinoma of the endometrium a – A case report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-17 14:23:48","doi":"10.21203/rs.3.rs-6410162/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"609ae39c-50f9-4ade-b77f-d394609da3e7","owner":[],"postedDate":"April 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":46900392,"name":"Oncology"},{"id":46900393,"name":"Internal Medicine"}],"tags":[],"updatedAt":"2025-04-17T14:23:48+00:00","versionOfRecord":[],"versionCreatedAt":"2025-04-17 14:23:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6410162","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6410162","identity":"rs-6410162","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}