Year End Projects in 2017

Itkin-Ansari Research Update: 12-2017

itkin-ansari_headshot

Background: Our lab made the discovery that a single bHLH protein can halt pancreatic cancer tumor growth in animals and reprogram the cells back to their original identity. To exploit this previously unrecognized plasticity in pancreatic cancer cells and translate our findings to the clinic we must identify a drug, or drugs, that will accomplish what we did genetically in the lab.

Therefore, we developed a platform to screen drugs for activation of bHLH signaling in PDA. From a screen of 4300 known drugs we chose 3 compounds for further testing.

 

Current: We are performing studies to determine the degree to which Drugs A, B and C can control cell growth, tumor suppressor signaling networks, cell fate, and bHLH protein signaling in pancreatic ductal adenocarcinoma (PDA) cells.  We have determined that Drug A inhibits cell proliferation in a dose dependent manner in both well-established pancreatic cancer lines as well as cells from a patient tumor.  Interestingly, the patient cells were the most sensitive to the drug at low doses.  At the mechanistic level Drug A blocks growth in all PDA cells tested by down regulation Aurora kinase A, cyclin A2 and topoisomerase 2A. Concurrently, Drug A induces expression of the cell cycle inhibitor p21 to restore the function of a key tumor suppressor protein, Retinoblastoma.  Retinoblastoma is rarely mutated in pancreatic cancer but is rendered nonfunctional by oncogene signaling.  Therefore, finding that we can restore Retinoblastoma activity in pancreatic cancer is very exciting.

Drug A was previously known to regulate cholesterol production, but we showed that in PDA cells, cholesterol production is not required for Drug A to induce p21. Because our screening platform provided a readout of bHLH protein activity, we also investigated the effects of Drug A on bHLH proteins of interest.  We determined for the first time that Drug A induces expression of the bHLH protein Dec-1, primarily in the nucleus. Moreover, Dec-1, like p21 was unaffected nu cholesterol levels.  Interestingly, Drug A did not consistently alter expression of the bHLH proteins Atoh8, SLUG, Twist, ID1, ID2, or ID3. Nor was there a consistent change in expression of E47 that we have shown to induce growth arrest and axinar reprogramming in PDA. However, the E47 target gene MIST1, that plays a critical role in axinar cell fate, was induced in 2 of the 3 PDA lines by Drug A.

We are now poised to investigate Drugs B and C. In early studies with Drug B, we find that it too induces p21 expression. Our ultimate goal is to determine whether any combination studies in animals.

Since receiving the Sky Foundation research award we have received a philanthropic pledge for $50,000 for pancreatic cancer research to be funded by the end of 2017.

Update published by Pamela Itkin-Ansari, PhD | Assistant Adjunct Professor | Development and Aging Program | Sanford-Burnham Prebys Medical Institute | Department of Pediatrics 

Pancreatic Cancer Action Update: Early Detection Initiative

Pancreatic Cancer Action Network logo. (PRNewsFoto/Pancreatic Cancer Action Network)

 

The chance of survival when detecting pancreatic cancer early enough is 40% for up-to five years; but when discovered late there is less than a 5% survival rate.

The foundation of Early Detection Initiative (EDI) is timely completion of the New Onset of Diabetes (NOD) cohort and support related research to translate results into clinical practice.

25% of patients diagnosed with pancreatic cancer have experienced NOD. It is important to conduct a study with an enriched high risk population so that the study can be more focused. There have been studies conducted to reveal that 40-50% of pancreatic cancer patients have diabetes and 50-80% of these patients were diagnosed with NOD.

Goal

  • Create research dataset
  • Screen patients
  • Show stage shift

Design

  • 10k patients, followed for 3 years
  • Recruit from Electronic Health Records (EHR) in integrated healthcare systems
  • Serial biospecimens to validate promising emerging biomarkers
  • Imaging CT or MRI

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