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Poster Display session 3

4489 - A Window of Opportunity Trial of Atorvastatin Targeting p53 Mutant Malignancies

Date

30 Sep 2019

Session

Poster Display session 3

Topics

Translational Research

Tumour Site

Presenters

Joaquina Baranda

Citation

Annals of Oncology (2019) 30 (suppl_5): v760-v796. 10.1093/annonc/mdz268

Authors

J.C. Baranda1, A. Bur2, T. Tsue2, L. Shnayder2, K. Kakarala2, M. Telfah3, T. Lin4, S.K. Williamson5, M. Al-Kasspooles6, J. Ashcraft6, N. Lakis7, R. Madan7, Q. Khan3, A. Saeed3, G. Reed8, S. Weir9, A. Godwin10, S. Thomas2, T. Komiya11, T. Iwakuma12

Author affiliations

  • 1 Early Phase Program, University of Kansas Cancer Center, 66205 - Fairway/US
  • 2 Ent, University of Kansas Medical Center, 66160 - Kansas City/US
  • 3 Medical Oncology, University of Kansas Cancer Center, 66205 - Westwood/US
  • 4 Hematologic Malignancies And Cellular Therapeutics, University of Kansas Cancer Center, 66205 - Fairway/US
  • 5 Medical Oncology, University of Kansas Cancer Center, 66205 - Fairway/US
  • 6 Surgical Oncology, University of Kansas Medical Center, 66160 - Kansas City/US
  • 7 Pathology, University of Kansas Medical Center, 66160 - Kansas City/US
  • 8 Clinical Pharmacology, University of Kansas Cancer Center, 66160 - Kansas City/US
  • 9 Pharmacology, Toxicology And Therapeutics, University of Kansas Medical Center, 66160 - Kansas City/US
  • 10 Pathology And Laboratory Medicine, University of Kansas Cancer Center, 66160 - Kansas City/US
  • 11 Medical Oncology, Parkview Cancer Institute, 46845 - Fort Wayne/US
  • 12 Cancer Biology, University of Kansas Medical Center, 66160 - Kansas City/US

Resources

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Abstract 4489

Background

p53 plays a critical role in cell cycle regulation, DNA repair, and apoptosis. To date, there are no effective therapeutic means to target mutant (mut) p53. Preclinical data from University of Kansas Cancer Center showed that several statins, like atorvastatin, suppress mutp53 level and cell growth selectively (PMID: 27775703). These effects were limited to mutations that affect conformation of p53 protein, while wild-type (wt) and DNA contact mutp53 were not as sensitive to statin-induced degradation. Statins are widely used for cardiovascular indications and are well tolerated. To translate this finding to the clinic, we designed this window of opportunity trial testing whether atorvastatin (A) can selectively suppress level of conformationally mutant (cmut) p53 protein in subjects with resectable tumors or previously treated Acute Myeloid Leukemia (AML).

Trial design

This is an open-label, pilot trial to determine if A will decrease level of cmutp53 protein in tissues of subjects with malignant diseases. Subjects with new diagnosis of solid malignancies in which treatment (tx) plan includes surgery as primary therapy and subjects with previously treated AML are eligible. Tumor tissues from subjects with solid tumors, and bone marrow or peripheral blood samples from subjects with AML are screened for p53 using immunohistochemistry (IHC). Eligible subjects receive A at 80 mg/day orally for 1-4 weeks. Using a 141 gene NGS panel, including TP53, the presence of cmutp53 is determined in pre-tx biopsy specimens or bone marrow/blood samples for AML patients. To assess the activity of A, pre-tx and post-tx levels of cmutp53 are compared side by side using IHC. Pharmacokinetic levels of A are also being measured. The primary objective is to determine if A will decrease level of cmutp53 in solid tumors and AML. Secondary objective is to assess effects of A on Ki-67 and caspase-3 in cmutp53 malignancies as well as in non-cmut and wtp53. The trial opened in June 2018, is accruing and continuing as planned. This proof-of-concept trial may lead to further investigations to define the role of A in personalizing tx of pts with cmutp53 tumors.

Clinical trial identification

NCT03560882.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

University of Kansas Cancer Center; NIH R01 CA214916 (T.I.).

Disclosure

All authors have declared no conflicts of interest.

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