ADAR1 Expression Level in Rectal Cancer

NCT07108348 | Recruiting

• 2 other identifiers: 24948/2025/5785Turkish Society of Med. Onc.
• Study Type: observational
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

Total neoadjuvant therapy (TNT) is currently the standard treatment for locally/locally advanced rectal cancer due to better response and fewer distant metastases. In TNT, sequential chemotherapy (CT) and chemoradiotherapy (CRT) are planned and depending on the treatment response, either surgery is performed or a watch and wait approach is applied. Depending on tumor localization and patient performance status, CT is planned as induction or consolidation. Most of the time, mFOLFOX6 and CAPOX are preferred as CT regimen. In proximal rectal cancer, surgery can be performed without CRT and only after CT. In locally/locally advanced rectal cancer, the aim is to avoid surgery as much as possible or to perform sphincter-sparing surgery if possible. Colonoscopy and pelvic MR at the time of diagnosis are the most important steps in staging, treatment selection and decision making. These two diagnostic methods should be repeated especially for watch and wait decision and for response evaluation after TNT. ADAR 1 (Adenosine deaminase acting on RNA1) is an RNA editing enzyme that catalyzes the deamination of adenosine to inosine (A-to-I), a dynamic modification that can lead to a diverse transcriptome in a combinatorial manner. A defect in ADAR1-mediated RNA modification results in abnormal regulation of substrates that can affect phenotypic changes in cancer. This phenomenon of over-regulation is seen in many cancers such as colon, liver, lung, breast and esophageal cancers and in many cases promotes tumor progression. In studies, increased ADAR1 expression has been associated with lower survival and worse prognosis, especially in metastatic colon and gastric cancer. ADAR1 is also predicted to increase proliferation through both the AKT pathway and the mTOR pathway and therefore may be targeted in the near future. ADAR1 expression is monitored by RNA-based real time PCR. In order to demonstrate increased expression, biopsies should be taken from the malignant tissue and the intact tissue of the patient and the biopsy should be stored under -80 C conditions immediately after biopsy to prevent RNA degradation. The tissue will not come into contact with nitrogen or formaldehyde. In this study, sufficient biopsies from cancerous and intact tissue will be taken from patients with suspected rectal cancer, confirmed by pelvic MRI and consent for participation in the study, and fresh tissue will be stored at -80 C in the genetics laboratory. After the TNT plan is made by the investigators and the treatment is completed, both pelvic MRI and control rectoscopy will be performed for preoperative evaluation. Again, biopsies will be taken from diseased and healthy tissue and ADAR1 expression will be evaluated. The study is planned to include 50 participants and a period of one year is foreseen for tissue procurement/storage. The investigators' aim in this study will be to determine whether ADAR1 expression level changes after TNT, whether this predicts clinical and pathological response, whether responses change according to the selected CT, whether there is a difference between CT induction-consolidation/RT short or long course, and the relationship between tumor DNA mismatch repair enzyme status and ADAR1 level. The investigators primary endpoint will be the effect of the change in ADAR1 expression level on the response after TNT (ORR). Secondary endpoints will be quality of life, recurrence-free survival (RFS) and overall survival (OS).

Conditions

Rectum Cancer, Adenocarcinoma

Keywords

ADAR1; rectum cancer; TNT

Outcome Measures

Primary Outcomes (1)

• Objective response rate according to RECIST 1.1

  Evaluation of target lesions Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this may include the baseline sum). The sum must also demonstrate an absolute increase of at least 5 mm. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

  From enrollment to the end of treatment at 12 weeks

Secondary Outcomes (2)

• Recurrence free survival

  Disease-free survival is evaluated up to 120 months after the first documented progression or death from any cause (whichever comes first) following surgery or watch and wait decision after TNT.

• Assessment of Quality of Life

  every 3 months for 1 year.

Study Arms (1)

50 patients with locally advanced rectal adenocarcinoma scheduled for TNT.

Biopsies will be taken from these 50 patients at the time of diagnosis and after TNT. The relationship between ADAR1 expression levels and TNT response will be investigated.

Genetic: Adenosine deaminase acting on RNA1

Interventions

Adenosine deaminase acting on RNA1 GENETIC

Previous studies have demonstrated that increased ADAR1 expression is associated with poor survival in gastric and metastatic colon cancer. In rectal cancer, however, the relationship between ADAR1 levels and TNT response in locally advanced disease has not been investigated. Another point is that ADAR1 can also be studied using immunohistochemistry; however, its sensitivity and specificity are low, so in our study, RNA will be isolated and analyzed using real-time PCR.

50 patients with locally advanced rectal adenocarcinoma scheduled for TNT.

Eligibility Criteria

• Age: 18 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Patients diagnosed with locally advanced rectal cancer who presented to the medical oncology, radiation oncology, and general surgery clinics of Necmettin Erbakan University Faculty of Medicine Hospital.

You may qualify if:

• Histological and staging diagnosis of local/locally advanced rectal cancer
• ECOG performance score between 0 and 2
• No contraindications for chemotherapy (CT) and/or radiotherapy (RT)

You may not qualify if:

• Those diagnosed with metastatic rectal cancer
• Those suspected of having rectal cancer or patients with a diagnosis of a second primary cancer
• Those who have not signed the informed consent form
• Those with contraindications for chemotherapy (CT) and/or radiation therapy (RT)

Sponsors & Collaborators

• Necmettin Erbakan University: lead
• Turkish Society of Medical Oncology: collaborator

Study Sites (1)

Necmettin Erbakan University Faculty of Medicine, Departmen of Medical Oncology

Konya, Meram, 42090, Turkey (Türkiye)

RECRUITING

Related Publications (8)

• Wang Q, Li X, Qi R, Billiar T. RNA Editing, ADAR1, and the Innate Immune Response. Genes (Basel). 2017 Jan 18;8(1):41. doi: 10.3390/genes8010041.

  PMID: 28106799 RESULT

• Okugawa Y, Toiyama Y, Shigeyasu K, Yamamoto A, Shigemori T, Yin C, Ichikawa T, Yasuda H, Fujikawa H, Yoshiyama S, Hiro J, Ohi M, Araki T, Kusunoki M, Goel A. Enhanced AZIN1 RNA editing and overexpression of its regulatory enzyme ADAR1 are important prognostic biomarkers in gastric cancer. J Transl Med. 2018 Dec 18;16(1):366. doi: 10.1186/s12967-018-1740-z.

  PMID: 30563560 RESULT

• Shigeyasu K, Okugawa Y, Toden S, Miyoshi J, Toiyama Y, Nagasaka T, Takahashi N, Kusunoki M, Takayama T, Yamada Y, Fujiwara T, Chen L, Goel A. AZIN1 RNA editing confers cancer stemness and enhances oncogenic potential in colorectal cancer. JCI Insight. 2018 Jun 21;3(12):e99976. doi: 10.1172/jci.insight.99976. eCollection 2018 Jun 21.

  PMID: 29925690 RESULT

• Chan TH, Lin CH, Qi L, Fei J, Li Y, Yong KJ, Liu M, Song Y, Chow RK, Ng VH, Yuan YF, Tenen DG, Guan XY, Chen L. A disrupted RNA editing balance mediated by ADARs (Adenosine DeAminases that act on RNA) in human hepatocellular carcinoma. Gut. 2014 May;63(5):832-43. doi: 10.1136/gutjnl-2012-304037. Epub 2013 Jun 13.

  PMID: 23766440 RESULT

• Eisenberg E, Levanon EY. A-to-I RNA editing - immune protector and transcriptome diversifier. Nat Rev Genet. 2018 Aug;19(8):473-490. doi: 10.1038/s41576-018-0006-1.

  PMID: 29692414 RESULT

• Chua YJ, Barbachano Y, Cunningham D, Oates JR, Brown G, Wotherspoon A, Tait D, Massey A, Tebbutt NC, Chau I. Neoadjuvant capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision in MRI-defined poor-risk rectal cancer: a phase 2 trial. Lancet Oncol. 2010 Mar;11(3):241-8. doi: 10.1016/S1470-2045(09)70381-X. Epub 2010 Jan 25.

  PMID: 20106720 RESULT

• Glynne-Jones R, Grainger J, Harrison M, Ostler P, Makris A. Neoadjuvant chemotherapy prior to preoperative chemoradiation or radiation in rectal cancer: should we be more cautious? Br J Cancer. 2006 Feb 13;94(3):363-71. doi: 10.1038/sj.bjc.6602960.

  PMID: 16465172 RESULT

• Aref A, Abdalla A. Erratum: Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer: Induction or Consolidation Chemotherapy? J Clin Oncol. 2025 Mar;43(7):898. doi: 10.1200/JCO-25-00095. Epub 2025 Jan 24. No abstract available.

  PMID: 39854654 RESULT

Related Links

• ADAR1 in colon cancer

Biospecimen

Retention: SAMPLES WITH DNA

Total RNA will be isolated from tissue samples stored at -80°C. In this process, 5-30 mg of tissue will be homogenized in a 1.5 mL homogenization tube, and then the extraction process will be performed according to the kit manufacturer's instructions, resulting in 30-50 μl of Total RNA. cDNA will be obtained from the RNA samples whose quantities have been calculated. In the PCR protocol, primer binding will be performed at 25°C for 10 minutes, reverse transcription will be performed at 42°C for 15 minutes, and finally, enzyme inactivation will be performed at 85°C for 5 minutes. Gene expression levels will be determined by the real-time PCR method. The p150 isoform, which is larger in size and has been used in previous studies, will be used. The reaction will be performed in a real-time PCR machine with an initial denaturation step at 95°C for 5 minutes, followed by 40 cycles of 95°C for 5 seconds, 55°C/59°C for 30 seconds (reading).

MeSH Terms

Conditions

Rectal Neoplasms

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases

Study Officials

• Mehmet Artaç, MD

  Necmettin Erbakan University Faculty of Medicine, Department of Medical Oncology

  STUDY DIRECTOR

Central Study Contacts

Ahmet Oruç, MD

CONTACT

+90 0505 704 50 20; mdahmetoruc@gmail.com

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Target Duration: 12 Months
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: July 1, 2025
• First Posted: August 7, 2025
• Study Start: June 1, 2025
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): September 1, 2026
• Last Updated: August 7, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: It will be ready in September 2026 and can be shared within the following year.
• Access Criteria: The statistical methods used for objective response rates, survival data, and quality of life outcomes can be reviewed by an independent review.

Locations

TU (1)