Clinical trial NCT06887673: Lipid Mediators & Cancer: Montelukast, SPM, and Almonds
Official title: Exploring the Impact of Montelukast, SPM, and/or Almond/Almond Oil Supplementation on Lipid Mediator Biosynthesis in Colorectal, Sarcomas, Brain Tumors, Endometrial, and Ovarian Cancer: A Pilot Study
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: EARLY_PHASE1
Conditions: Colorectal Cancer
Sarcoma
Brain Tumors
Endometrial Cancer
Ovarian Cancer
Keywords: Montelukast
Almonds/Almond oil
Specialized pro-resolving mediators
Tumor-associated macrophages
Lipid mediators
Colorectal cancer
Inflammation
Lead sponsor: University of South Florida
Sponsor class: OTHER
First posted: 2025-03-20
Enrollment: 56
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to create a prospective investigation to examine the effects of montelukast, almonds/almond oil, and specialized pro-resolving mediators (SPMs) on lipid profiles and tumor-associated macrophages (TAMs) in cancer patients (colorectal cancer, sarcoma, brain tumors, endometrial cancer, and ovarian cancer). The focus will be on assessing changes in lipid mediator concentrations, TAM reprogramming, and immune cell function in treated versus untreated patients. It is hypothesized that montelukast will reduce the pro-inflammatory effects of leukotriene B4 (LTB4), while SPMs and almonds/almond oil will shift the balance toward pro-resolving mediators, enhancing anti-inflammatory and immune-stimulatory responses and reprogramming TAMs.

Detailed description: This prospective study investigates the effects of montelukast, almonds/almond oil, and specialized pro-resolving mediators (SPMs) on lipid profiles and tumor-associated macrophages (TAMs) in patients with colorectal cancer (CRC), sarcoma, brain tumors (BT), endometrial cancer (EC), and ovarian cancer (OvCa). Patients receiving these treatments will be compared to untreated controls, with tissue samples collected post-surgery for analysis. A cohort of patients who have undergone tumor resection will be included for the assessment of lipid mediator concentrations (approximately 65 arachidonic acid pathway lipids) and TAM reprogramming, with an emphasis on comparing treated and untreated groups. The study will also examine peripheral blood mononuclear cells (PBMCs) and plasma concentrations of lipid mediators before and after treatment, focusing on changes in PBMC function and phenotype. It is hypothesized that montelukast, an LTB4/ cysteinyl leukotriene receptor 1 (CYSLTR1) inhibitor, will reduce the pro-inflammatory effects of LTB4 in cancer tissues. Furthermore, it is anticipated that SPMs and almonds/almond oil will shift the lipid mediator balance toward pro-resolving mediators, enhancing anti-inflammatory responses, stimulating immune function, and reprogramming TAMs.

Eligibility criteria: Inclusion Criteria:

1. Newly diagnosed individuals with stages I-IV colorectal or ovarian cancer, grade 1 and 2 endometrial cancer, as well as those with brain tumors or sarcoma.
2. Participants scheduled for surgical intervention at least two (2) weeks from the day of enrollment.
3. Patients must be able to understand and willing to sign a written informed consent document for both this study and the University of South Florida (USF)/ Tampa General Hospital (TGH) Biorepository study (STUDY000356).
4. Age 18 or older.

Exclusion Criteria:

1. Inability to give consent due to a mental condition that makes the participant unable to understand the study's nature, scope, and possible consequences.
2. Participants who are unlikely to adhere to the protocol as determined by the study investigator.
3. Allergy to fish, seafood, aspirin, NSAIDs, montelukast, or nuts
4. Participants with a history of asthma or chronic obstructive pulmonary disease (COPD).
5. Patients with a history of phenylketonuria (PKU).
6. Participants with a history of a psychiatric illness (e.g., major depression, anxiety disorder, bipolar disorder, obsessive-compulsive disorder, etc.).
7. Surgical intervention scheduled more than eight (8) weeks from the initial enrollment day.
8. No evidence of a discrete mass on endoscopy or radiologic imaging
9. Concomitant existence of other malignancies
10. Uncontrolled hypertension or diabetes mellitus
11. Chronic Liver Disease or cirrhosis
12. Liver function impairment or persisting elevations (confirmed by retest) of alanine aminotransferase (ALT), aspartate aminotransferase (AST), or direct bilirubin greater than 2x the upper limit of the normal range (ULN)
13. Bleeding conditions such as disorders of platelet function, idiopathic thrombocytopenia purpura (ITP), thrombotic thrombocytopenic purpura (TTP), hemophilia or any clotting factor deficiency, von Willebrand disease or Glanzmann disease among other
14. Use of antiplatelet or anticoagulant medications, including aspirin, clopidogrel, warfarin, direct oral anticoagulants (DOACs), and heparin, among others
15. Persistent significant or severe infection, either acute or chronic
16. Participants with significantly impaired bone marrow function or significant anemia, leukopenia, or thrombocytopenia (confirmed by retest):

    1. Hematocrit \< 35% and/or
    2. Absolute white blood cell count \< 3000 cells/mm3 (μL) and/or
    3. Platelet count \< 150 000 cells/mm3 (μL) and/or
    4. Absolute neutrophil ≤ 1500 cells/mm3 (μL)
17. Chronic use of immunosuppressive medications
18. History of organ transplantation
19. Emergency surgery
20. Pregnant or breast-feeding women or those who plan to become pregnant during the study.
21. Women of childbearing potential who are not protected by effective contraceptive methods of birth control and/or are unwilling or unable to be tested for pregnancy.
22. Prisoners
23. Participants who have received treatment with leukotriene inhibitors, taken omega-3 supplements, or eaten almonds within the last 4 weeks.
24. Prior use of any investigational drug in the preceding six (6) months
25. Participants who, after being enrolled in this study and assigned a particular study treatment, consume products involved in other study cohorts other than what they were assigned (i.e. if a patient is assigned to take SPMs as their study treatment but during the course of the study also is consuming daily almonds)
26. Participants who are unable to swallow oral medication or chew almonds.
27. Participants who have already started neoadjuvant therapies for their cancer diagnosis

Primary outcomes:
measure: Quantity of lipid mediators in a tumor specimen after 2 weeks of study treatment.
timeFrame: Day 14 of treatment
measure: Quantity of lipid mediators in a non-cancerous (i.e. normal) tissue from the resected surgical specimen after 2 weeks of study treatment.
timeFrame: Day 14 of treatment
Secondary outcomes:
measure: Quantity of tumor microenvironment subpopulations in a tumor specimen versus corresponding normal tissue after 2 weeks of study treatment.
timeFrame: Day 14 of treatment
measure: Distribution of tumor-associated macrophage (TAM) phenotype in tumor specimens versus corresponding normal tissue after 2 weeks of study treatment.
timeFrame: Day 14 of treatment
measure: Functionality of tumor-associated macrophages in tumor specimens versus corresponding normal tissue after 2 weeks of study treatment.
timeFrame: Day 14 of treatment
measure: Change in quantity of lipids in peripheral blood from day 0 to day 14 of study treatment.
timeFrame: Day 0 and Day 14
Other outcomes:
Locations:
city: Tampa
country: United States
facility: Tampa General Hospital
state: Florida
city: Tampa
country: United States
facility: University of South Florida
state: Florida
Study officials:
affiliation: University of South Florida
name: Jorge Marcet
role: PRINCIPAL_INVESTIGATOR
References:
citation: Prasad S, Sung B, Aggarwal BB. Age-associated chronic diseases require age-old medicine: role of chronic inflammation. Prev Med. 2012 May;54 Suppl(Suppl):S29-37. doi: 10.1016/j.ypmed.2011.11.011. Epub 2011 Dec 9.
citation: Serhan CN. Discovery of specialized pro-resolving mediators marks the dawn of resolution physiology and pharmacology. Mol Aspects Med. 2017 Dec;58:1-11. doi: 10.1016/j.mam.2017.03.001. Epub 2017 Mar 3.
citation: Song M, Zhang X, Meyerhardt JA, Giovannucci EL, Ogino S, Fuchs CS, Chan AT. Marine omega-3 polyunsaturated fatty acid intake and survival after colorectal cancer diagnosis. Gut. 2017 Oct;66(10):1790-1796. doi: 10.1136/gutjnl-2016-311990. Epub 2016 Jul 19.
citation: Daniel CR, McCullough ML, Patel RC, Jacobs EJ, Flanders WD, Thun MJ, Calle EE. Dietary intake of omega-6 and omega-3 fatty acids and risk of colorectal cancer in a prospective cohort of U.S. men and women. Cancer Epidemiol Biomarkers Prev. 2009 Feb;18(2):516-25. doi: 10.1158/1055-9965.EPI-08-0750. Epub 2009 Feb 3.
citation: Shin A, Cho S, Sandin S, Lof M, Oh MY, Weiderpass E. Omega-3 and -6 Fatty Acid Intake and Colorectal Cancer Risk in Swedish Women's Lifestyle and Health Cohort. Cancer Res Treat. 2020 Jul;52(3):848-854. doi: 10.4143/crt.2019.550. Epub 2020 Mar 6.
citation: Schloss I, Kidd MS, Tichelaar HY, Young GO, O'Keefe SJ. Dietary factors associated with a low risk of colon cancer in coloured west coast fishermen. S Afr Med J. 1997 Feb;87(2):152-8.
citation: Petrik MB, McEntee MF, Chiu CH, Whelan J. Antagonism of arachidonic acid is linked to the antitumorigenic effect of dietary eicosapentaenoic acid in Apc(Min/+) mice. J Nutr. 2000 May;130(5):1153-8. doi: 10.1093/jn/130.5.1153.
citation: Fini L, Piazzi G, Ceccarelli C, Daoud Y, Belluzzi A, Munarini A, Graziani G, Fogliano V, Selgrad M, Garcia M, Gasbarrini A, Genta RM, Boland CR, Ricciardiello L. Highly purified eicosapentaenoic acid as free fatty acids strongly suppresses polyps in Apc(Min/+) mice. Clin Cancer Res. 2010 Dec 1;16(23):5703-11. doi: 10.1158/1078-0432.CCR-10-1990. Epub 2010 Oct 28.
citation: Nowak J, Weylandt KH, Habbel P, Wang J, Dignass A, Glickman JN, Kang JX. Colitis-associated colon tumorigenesis is suppressed in transgenic mice rich in endogenous n-3 fatty acids. Carcinogenesis. 2007 Sep;28(9):1991-5. doi: 10.1093/carcin/bgm166. Epub 2007 Jul 18.
citation: West NJ, Clark SK, Phillips RK, Hutchinson JM, Leicester RJ, Belluzzi A, Hull MA. Eicosapentaenoic acid reduces rectal polyp number and size in familial adenomatous polyposis. Gut. 2010 Jul;59(7):918-25. doi: 10.1136/gut.2009.200642. Epub 2010 Mar 26.
citation: Liang B, Wang S, Ye YJ, Yang XD, Wang YL, Qu J, Xie QW, Yin MJ. Impact of postoperative omega-3 fatty acid-supplemented parenteral nutrition on clinical outcomes and immunomodulations in colorectal cancer patients. World J Gastroenterol. 2008 Apr 21;14(15):2434-9. doi: 10.3748/wjg.14.2434.
citation: Sorensen LS, Thorlacius-Ussing O, Rasmussen HH, Lundbye-Christensen S, Calder PC, Lindorff-Larsen K, Schmidt EB. Effects of perioperative supplementation with omega-3 fatty acids on leukotriene B(4) and leukotriene B(5) production by stimulated neutrophils in patients with colorectal cancer: a randomized, placebo-controlled intervention trial. Nutrients. 2014 Sep 29;6(10):4043-57. doi: 10.3390/nu6104043.
citation: Manda K, Kriesen S, Hildebrandt G, Fietkau R, Klautke G. Omega-3 fatty acid supplementation in cancer therapy : does eicosapentanoic acid influence the radiosensitivity of tumor cells? Strahlenther Onkol. 2011 Feb;187(2):127-34. doi: 10.1007/s00066-010-2166-6. Epub 2011 Jan 18.
citation: West L, Yin Y, Pierce SR, Fang Z, Fan Y, Sun W, Tucker K, Staley A, Zhou C, Bae-Jump V. Docosahexaenoic acid (DHA), an omega-3 fatty acid, inhibits tumor growth and metastatic potential of ovarian cancer. Am J Cancer Res. 2020 Dec 1;10(12):4450-4463. eCollection 2020.
citation: Kuznetsova L, Chen J, Sun L, Wu X, Pepe A, Veith JM, Pera P, Bernacki RJ, Ojima I. Syntheses and evaluation of novel fatty acid-second-generation taxoid conjugates as promising anticancer agents. Bioorg Med Chem Lett. 2006 Feb 15;16(4):974-7. doi: 10.1016/j.bmcl.2005.10.089. Epub 2005 Nov 18.
citation: Wang YC, Wu YN, Wang SL, Lin QH, He MF, Liu QL, Wang JH. Docosahexaenoic Acid Modulates Invasion and Metastasis of Human Ovarian Cancer via Multiple Molecular Pathways. Int J Gynecol Cancer. 2016 Jul;26(6):994-1003. doi: 10.1097/IGC.0000000000000746.
citation: Wen Z, Liu H, Li M, Li B, Gao W, Shao Q, Fan B, Zhao F, Wang Q, Xie Q, Yang Y, Yu J, Qu X. Increased metabolites of 5-lipoxygenase from hypoxic ovarian cancer cells promote tumor-associated macrophage infiltration. Oncogene. 2015 Mar 5;34(10):1241-52. doi: 10.1038/onc.2014.85. Epub 2014 Mar 24.
citation: Wang Y, Liu K, Long T, Long J, Li Y, Li J, Cheng L. Dietary fish and omega-3 polyunsaturated fatty acids intake and cancer survival: A systematic review and meta-analysis. Crit Rev Food Sci Nutr. 2023;63(23):6235-6251. doi: 10.1080/10408398.2022.2029826. Epub 2022 Jan 24.
citation: Jang HY, Kim IW, Oh JM. Cysteinyl Leukotriene Receptor Antagonists Associated With a Decreased Incidence of Cancer: A Retrospective Cohort Study. Front Oncol. 2022 Apr 7;12:858855. doi: 10.3389/fonc.2022.858855. eCollection 2022.
citation: Higurashi T, Ashikari K, Tamura S, Saigusa Y, Takatsu T, Misawa N, Yoshihara T, Matsuura T, Fuyuki A, Ohkubo H, Kessoku T, Hosono K, Yoneda M, Nakajima A. Leukotriene Receptor Antagonist Therapy for the Chemoprevention of Human Rectal Aberrant Crypt Foci: Nonrandomized, Open-Label, Controlled Trial. Cancer Prev Res (Phila). 2022 Oct 4;15(10):661-668. doi: 10.1158/1940-6207.CAPR-22-0049.
citation: Lien EL. Toxicology and safety of DHA. Prostaglandins Leukot Essent Fatty Acids. 2009 Aug-Sep;81(2-3):125-32. doi: 10.1016/j.plefa.2009.05.004. Epub 2009 Jun 6.
citation: Villani AM, Crotty M, Cleland LG, James MJ, Fraser RJ, Cobiac L, Miller MD. Fish oil administration in older adults: is there potential for adverse events? A systematic review of the literature. BMC Geriatr. 2013 May 1;13:41. doi: 10.1186/1471-2318-13-41.
citation: Souza PR, Marques RM, Gomez EA, Colas RA, De Matteis R, Zak A, Patel M, Collier DJ, Dalli J. Enriched Marine Oil Supplements Increase Peripheral Blood Specialized Pro-Resolving Mediators Concentrations and Reprogram Host Immune Responses: A Randomized Double-Blind Placebo-Controlled Study. Circ Res. 2020 Jan 3;126(1):75-90. doi: 10.1161/CIRCRESAHA.119.315506. Epub 2019 Dec 12.
citation: FDA. FDA requires stronger warning about risk of neuropsychiatric events associated with asthma and allergy drug montelukast. . Published March 4, 2020. Accessed February 18, 2023. https://www.fda.gov/news-events/press-announcements/fda-requires-stronger-warning-about-risk-neuropsychiatric-events-associated-asthma-and-allergy
citation: Aldea Perona A, Garcia-Saiz M, Sanz Alvarez E. Psychiatric Disorders and Montelukast in Children: A Disproportionality Analysis of the VigiBase((R)). Drug Saf. 2016 Jan;39(1):69-78. doi: 10.1007/s40264-015-0360-2.
citation: Benard B, Bastien V, Vinet B, Yang R, Krajinovic M, Ducharme FM. Neuropsychiatric adverse drug reactions in children initiated on montelukast in real-life practice. Eur Respir J. 2017 Aug 17;50(2):1700148. doi: 10.1183/13993003.00148-2017. Print 2017 Aug.
citation: Ali MM, O'Brien CE, Cleves MA, Martin BC. Exploring the possible association between montelukast and neuropsychiatric events among children with asthma: a matched nested case-control study. Pharmacoepidemiol Drug Saf. 2015 Apr;24(4):435-45. doi: 10.1002/pds.3758. Epub 2015 Feb 12.
citation: Sansing-Foster V, Haug N, Mosholder A, Cocoros NM, Bradley M, Ma Y, Pennap D, Dee EC, Toh S, Pestine E, Petrone AB, Kim I, Lyons JG, Eworuke E. Risk of Psychiatric Adverse Events Among Montelukast Users. J Allergy Clin Immunol Pract. 2021 Jan;9(1):385-393.e12. doi: 10.1016/j.jaip.2020.07.052. Epub 2020 Aug 11.
citation: Knapp HR, Reilly IA, Alessandrini P, FitzGerald GA. In vivo indexes of platelet and vascular function during fish-oil administration in patients with atherosclerosis. N Engl J Med. 1986 Apr 10;314(15):937-42. doi: 10.1056/NEJM198604103141501.
citation: Abdelhamid AS, Brown TJ, Brainard JS, Biswas P, Thorpe GC, Moore HJ, Deane KH, Summerbell CD, Worthington HV, Song F, Hooper L. Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2020 Feb 29;3(3):CD003177. doi: 10.1002/14651858.CD003177.pub5.
citation: Akintoye E, Sethi P, Harris WS, Thompson PA, Marchioli R, Tavazzi L, Latini R, Pretorius M, Brown NJ, Libby P, Mozaffarian D. Fish Oil and Perioperative Bleeding. Circ Cardiovasc Qual Outcomes. 2018 Nov;11(11):e004584. doi: 10.1161/CIRCOUTCOMES.118.004584.
citation: Mozaffarian D, Rimm EB. Fish intake, contaminants, and human health: evaluating the risks and the benefits. JAMA. 2006 Oct 18;296(15):1885-99. doi: 10.1001/jama.296.15.1885.
citation: Nicholls SJ, Lincoff AM, Garcia M, Bash D, Ballantyne CM, Barter PJ, Davidson MH, Kastelein JJP, Koenig W, McGuire DK, Mozaffarian D, Ridker PM, Ray KK, Katona BG, Himmelmann A, Loss LE, Rensfeldt M, Lundstrom T, Agrawal R, Menon V, Wolski K, Nissen SE. Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk: The STRENGTH Randomized Clinical Trial. JAMA. 2020 Dec 8;324(22):2268-2280. doi: 10.1001/jama.2020.22258.
citation: Nielsen CK, Ohd JF, Wikstrom K, Massoumi R, Paruchuri S, Juhas M, Sjolander A. The leukotriene receptor CysLT1 and 5-lipoxygenase are upregulated in colon cancer. Adv Exp Med Biol. 2003;525:201-4. doi: 10.1007/978-1-4419-9194-2_43. No abstract available.
citation: Burke L, Butler CT, Murphy A, Moran B, Gallagher WM, O'Sullivan J, Kennedy BN. Evaluation of Cysteinyl Leukotriene Signaling as a Therapeutic Target for Colorectal Cancer. Front Cell Dev Biol. 2016 Sep 21;4:103. doi: 10.3389/fcell.2016.00103. eCollection 2016.
citation: Sulciner ML, Serhan CN, Gilligan MM, Mudge DK, Chang J, Gartung A, Lehner KA, Bielenberg DR, Schmidt B, Dalli J, Greene ER, Gus-Brautbar Y, Piwowarski J, Mammoto T, Zurakowski D, Perretti M, Sukhatme VP, Kaipainen A, Kieran MW, Huang S, Panigrahy D. Resolvins suppress tumor growth and enhance cancer therapy. J Exp Med. 2018 Jan 2;215(1):115-140. doi: 10.1084/jem.20170681. Epub 2017 Nov 30.
citation: Ahmad Z. The uses and properties of almond oil. Complement Ther Clin Pract. 2010 Feb;16(1):10-2. doi: 10.1016/j.ctcp.2009.06.015. Epub 2009 Jul 15.
citation: Mericli F, Becer E, Kabadayi H, Hanoglu A, Yigit Hanoglu D, Ozkum Yavuz D, Ozek T, Vatansever S. Fatty acid composition and anticancer activity in colon carcinoma cell lines of Prunus dulcis seed oil. Pharm Biol. 2017 Dec;55(1):1239-1248. doi: 10.1080/13880209.2017.1296003.
citation: Hollis J, Mattes R. Effect of chronic consumption of almonds on body weight in healthy humans. Br J Nutr. 2007 Sep;98(3):651-6. doi: 10.1017/S0007114507734608. Epub 2007 Apr 20.
citation: Ali ZK, Sahib HB. Antiangiogenic Activity of Sweet Almond (Prunus dulcis) Oil Alone and in Combination with Aspirin in both in vivo and in vitro Assays. Asian Pac J Cancer Prev. 2022 Apr 1;23(4):1405-1413. doi: 10.31557/APJCP.2022.23.4.1405.
citation: Hyson DA, Schneeman BO, Davis PA. Almonds and almond oil have similar effects on plasma lipids and LDL oxidation in healthy men and women. J Nutr. 2002 Apr;132(4):703-7. doi: 10.1093/jn/132.4.703.
citation: Fraser GE, Sabate J, Beeson WL, Strahan TM. A possible protective effect of nut consumption on risk of coronary heart disease. The Adventist Health Study. Arch Intern Med. 1992 Jul;152(7):1416-24.
citation: Dreher ML. A Comprehensive Review of Almond Clinical Trials on Weight Measures, Metabolic Health Biomarkers and Outcomes, and the Gut Microbiota. Nutrients. 2021 Jun 8;13(6):1968. doi: 10.3390/nu13061968.
citation: Aune D, Keum N, Giovannucci E, Fadnes LT, Boffetta P, Greenwood DC, Tonstad S, Vatten LJ, Riboli E, Norat T. Nut consumption and risk of cardiovascular disease, total cancer, all-cause and cause-specific mortality: a systematic review and dose-response meta-analysis of prospective studies. BMC Med. 2016 Dec 5;14(1):207. doi: 10.1186/s12916-016-0730-3.