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Memorial Sloan Kettering Cancer Center

2013

Molecular analysis of FLC tumors

Goal: Conduct genomic-based analysis of FLC patients

Principal Investigator: Ron DeMatteo, MD

Grant length: Two years

Study background and overview: At the time of this effort, little was known about the exact mutations driving fibrolamellar carcinoma. Published research on the genomic alterations in FLC was scarce and limited to small studies, with the largest comprised of just 11 patients.

Without this knowledge, clinicians were unable to design or apply targeted therapies to FLC. As a major referral center for liver cancer patients, Memorial Sloan-Kettering had a unique position to study FLC. The study team proposed to conduct a genomic-based analysis in the largest cohort of FLC patients to date, using tissue samples from approximately 40 FLC patients who underwent resection surgery for primary or metastatic fibrolamellar cancer. Their goal was to identify the causes and drivers of FLC – laying the groundwork for development of novel and more effective treatments.

Key findings: The study analyzed 38 specimens from 26 patients by array comparative genomic hybridiziation (aCGH) and 35 specimens from 15 patients by transcriptome sequencing (RNA-seq). All the tumor specimens examined exhibited genomic instability, with a higher frequency of genomic amplifications or deletions in the metastatic tumors. They observed the DNAJB1-PRKACA fusion transcript in 26 of 26 tumor specimens from 15 FL-HCC patients, further strengthening the belief that the DNAJB1-PRKACA fusion plays a key role in tumorigenesis.

The regions encoding 71 microRNAs (miRs) were deleted in at least 25% of tumor specimens. Five of these recurrently deleted miRs targeted the insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) gene product, and a correlating 100-fold upregulation of IGF2BP1 mRNA was seen in tumor specimens. Analysis of the transcriptome demonstrated a high degree of similarity in all tumors from the same patients, independent of the recurrence site or time. The p53 tumor suppressor pathway was downregulated as demonstrated by both aCGH and RNA-seq analysis, despite the lack of a TP53 inactivating mutation in FLC. Notch, EGFR, NRAS, and RB1 pathways were also significantly dysregulated in tumors compared with normal liver tissue.

These results were published in PLOS ONE in May 2017. The full article can be accessed at https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0176562.

Implications: The study data indicates a role for p53 pathway inactivation and IGF2BP1 upregulation in FLC, both of which have important roles in conventional hepatocellular carcinoma pathogenesis as well. The results also suggest a mechanism for IGF2BP1 up regulation. The study also showed that FLC tumors are likely able to suppress p53 pathway activity by multiple alternative and potentially targetable means.

In addition, a case series on 37 patients with FLC treated at MSKCC was published in The British Journal of Radiology in April 2014. Details of that case study can be read here: https://www.birpublications.org/doi/10.1259/bjr.20140024.

2010

Everolimus clinical trial

Goal: Assess potential of everolimus (RAD001) as a treatment option for FLC

Principal Investigator: Ghassan Abou-Alfa, MD

Grant length: Three years

Study background and overview: At the time of this trial, the molecular drive of fibrolamellar, the DNAJB1-PRKACA fusion gene, had not been identified. However, several factors suggested that estrogen and estrogen-dependent pathways may play a role in FLC’s pathogenesis, including:

  • Case reports of gynecomastia as a presenting feature of FLC in young males
  • Documentation of aromatase overexpression in FLC tumors
  • The association of hyperestrogenic states including pregnancy and oral contraceptive use with FLC
  • Demonstration of increased mammalian target of rapamycin (mTOR) activity in FLC tumors by immunohistochemical staining.

Consequently, on the basis of interaction between estrogen and the PI3K/Akt/mTOR pathway, the team hypothesized that suppression of estrogen and mTOR signaling could stop FLC tumor cells from growing and dividing. The combination of letrozole, a drug that prevents estrogen production, and everolimus (RAD001), a drug that controls the cancer cell signals had previously been shown to be active and safe in breast cancer patients. The team therefore proposed a study testing the effectiveness of estrogen deprivation therapy and mTOR inhibition in patients with advanced FLC.

The resulting phase II trial randomized patients into the following three arms:

  • Arm A (everolimus),
  • Arm B (letrozole/leuprolide) – estrogen deprivation therapy, or
  • Arm C (everolimus/letrozole/leuprolide).

Upon disease progression, patients in arm A or B could transition to the everolimus/letrozole/leuprolide treatment.

Through this effort, FCF funded the first clinical trial of drugs aimed specifically at fibrolamellar carcinoma.  The trial was conducted Memorial Sloan Kettering, along with several other consortium members, including the University of California San Francisco, Johns Hopkins, and Dana Farber. Two major pharmaceutical companies donated the drugs investigated.  

Key findings: In total, 28 FLC patients were enrolled in this phase II trial. The study concluded that estrogen deprivation therapy with letrozole and leuprolide, alone or in combination with the mTOR inhibitor, everolimus, did not demonstrate clinical activity in advanced fibrolamellar carcinoma. Neither approach improved patient outcomes.

The results of the clinical trial were published in The Oncologist in May 2020. Click here to read the published results of the study.