Personalized treatment

Graphic showing DNA sequencing

This schematic shows the different mutations (missense, nonsense, frameshift, splice site) found in 76 putative pancreatic cancer driver genes from 58 patient samples. Copy number alterations are also shown.

The promise of precision medicine is the ability to tailor individual treatments to specific cancer-causing mutations (personalized treatment). However, there are no effective targeted treatments approved for pancreatic cancer currently.

Pancreatic cancer is an intractable malignancy with only a 9% survival rate beyond five years. Unlike most other malignancies, this survival rate has not significantly changed over the last 30 years. Given the desperate need for novel therapies, we are attacking the problem with a multi-disciplinary approach.

Mapping mutations

We are actively mapping the mutations that occur in pancreatic cancer and that may be driving cancer formation or progression. We sequence tumor DNA and RNA to identify germline or somatic mutations, as well as copy number alterations.

Some of the mutations identified are potentially actionable (for example, ATM, MYC, RNF43, BRAF, and CDK4), which means that targeted agents exist that might be effective. However, no systematic treatment with any agent has been performed for pancreatic cancer patients with these mutations.

We have recently treated a pancreatic cancer patient harboring a BRAF deletion with the MEK inhibitor trametinib and observed reduced tumor mass and liver metastasis. Additionally, a patient with a rare ROS1 translocation responded to crizotinib. Another patient carrying a BRCA2 mutation responded to the PARP inhibitor olaparib after folfirinox treatment, as the tumor mass is no longer visible. PARP inhibitors have shown promise for treatment of other cancers (breast and ovarian cancer, for example) with specific DNA repair deficiencies. We are currently enrolling patients for a PARP inhibitor clinical trial in metastatic pancreatic cancer (niraparib).

Living biobank

Using surgical resection or core needle biopsy, we are also supported by a Lustgarten grant to collect primary tumor specimens from patients for propagation in culture. Primary specimens are used to create a “living biobank” of patient-derived cell lines, tumor organoids, and patient-derived xenografts.

We then use these pre-clinical models to test known compounds or novel agents, either alone or in combination. We are testing to what extent patient-derived tumor organoids can be used for drug sensitivity assays that guide patient treatment strategies in real time.

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