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

Overview

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.

Interventions

• Other No Interventions
  No study treatment other than the standard of care management.
• Dietary supplement Sports Pro Resolve 4 g
  Sports Pro Resolve 4 tabs (2 g) twice daily
• Dietary supplement Double Wood SPM 4 g
  Double Wood SPM 4 tabs (2 g) twice daily
• Dietary supplement 20 California Sweet Almonds
  10 California Sweet Almonds twice daily
• Drug Montelukast 10 Mg Oral Tablet
  Montelukast 10 Mg Oral Tablet daily
• Combination product Montelukast 10 Mg Oral Tablet and SPM 4 g
  Montelukast 10 Mg Oral Tablet and SPM 4 g
• Dietary supplement Cold- Pressed Almond Oil 30 mL
  Cold- Pressed Almond Oil 30 mL every morning

Primary outcome measures

• Quantity of lipid mediators in a tumor specimen after 2 weeks of study treatment. [Time frame: Day 14 of treatment]
• Quantity of lipid mediators in a non-cancerous (i.e. normal) tissue from the resected surgical specimen after 2 weeks of study treatment. [Time frame: Day 14 of treatment]

Secondary outcome measures (4)

• Quantity of tumor microenvironment subpopulations in a tumor specimen versus corresponding normal tissue after 2 weeks of study treatment. [Time frame: Day 14 of treatment]
• Distribution of tumor-associated macrophage (TAM) phenotype in tumor specimens versus corresponding normal tissue after 2 weeks of study treatment. [Time frame: Day 14 of treatment]
• Functionality of tumor-associated macrophages in tumor specimens versus corresponding normal tissue after 2 weeks of study treatment. [Time frame: Day 14 of treatment]
• Change in quantity of lipids in peripheral blood from day 0 to day 14 of study treatment. [Time frame: Day 0 and Day 14]

Eligibility criteria

Inclusion criteria

• 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.
• Participants scheduled for surgical intervention at least two (2) weeks from the day of enrollment.
• 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).
• Age 18 or older.

Exclusion criteria

• Inability to give consent due to a mental condition that makes the participant unable to understand the study's nature, scope, and possible consequences.
• Participants who are unlikely to adhere to the protocol as determined by the study investigator.
• Allergy to fish, seafood, aspirin, NSAIDs, montelukast, or nuts
• Participants with a history of asthma or chronic obstructive pulmonary disease (COPD).
• Patients with a history of phenylketonuria (PKU).
• Participants with a history of a psychiatric illness (e.g., major depression, anxiety disorder, bipolar disorder, obsessive-compulsive disorder, etc.).
• Surgical intervention scheduled more than eight (8) weeks from the initial enrollment day.
• No evidence of a discrete mass on endoscopy or radiologic imaging
• Concomitant existence of other malignancies
• Uncontrolled hypertension or diabetes mellitus
• Chronic Liver Disease or cirrhosis
• 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)
• 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
• Use of antiplatelet or anticoagulant medications, including aspirin, clopidogrel, warfarin, direct oral anticoagulants (DOACs), and heparin, among others
• Persistent significant or severe infection, either acute or chronic
• Participants with significantly impaired bone marrow function or significant anemia, leukopenia, or thrombocytopenia (confirmed by retest):

• Hematocrit < 35% and/or
• Absolute white blood cell count < 3000 cells/mm3 (μL) and/or
• Platelet count < 150 000 cells/mm3 (μL) and/or
• Absolute neutrophil ≤ 1500 cells/mm3 (μL)
• Chronic use of immunosuppressive medications
• History of organ transplantation
• Emergency surgery
• Pregnant or breast-feeding women or those who plan to become pregnant during the study.
• 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.
• Prisoners
• Participants who have received treatment with leukotriene inhibitors, taken omega-3 supplements, or eaten almonds within the last 4 weeks.
• Prior use of any investigational drug in the preceding six (6) months
• 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)
• Participants who are unable to swallow oral medication or chew almonds.
• Participants who have already started neoadjuvant therapies for their cancer diagnosis

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 2 centers

• Tampa General Hospital — Tampa
• University of South Florida — Tampa

Publications

• 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. PMID 22178471
• 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. PMID 28263773
• 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. PMID 27436272
• 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. PMID 19190143
• 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. PMID 32138465
• 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. PMID 9107220
• 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. PMID 10801912
• 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. PMID 21030497

Identifiers

NCT: NCT06887673 · STUDY006089

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗