Pancreatic Cancer Treatment Targets
Nat Pernick, M.D.
29 August 2021
Histologic type: Pancreatic adenocarcinoma, NOS
Stages: all
5 year survival: 10%, see
https://www.cancer.org/cancer/pancreatic-cancer/detection-diagnosis-staging/survival-rates.html
Our strategic plan suggests that there exists a large combination (perhaps 8-10) of partially effective
treatments against pancreatic cancer that will produce high rates of long term survival even though the
individual treatments will not (http://www.natpernick.com/StrategicPlanCuringCancer.html). The set of
therapies to choose from may need to total 30 or more. Although we cannot predict which of the millions
of possible combinations will be most effective, the use of machine learning, cell lines and animal models
may be helpful. We also suggest using therapies focusing not just on the cancer cells, but on the cancer
microenvironment, chronic inflammation, hormones (for some cancers), immune system dysfunction,
relevant germline variations and risk factors, both behavioral and non behavioral.
Below is our current list of partially effective treatments for pancreatic adenocarcinoma followed by
malignant attributes that we consider worthy of further investigation:
1. Partially effective treatments
Surgery
* Surgery is potentially curative for patients with resectable or borderline resectable pancreatic cancer,
https://www.cancer.gov/types/pancreatic/hp/pancreatic-treatment-pdq#_99 .
* Typically surgery is more effective when combined with chemotherapy or chemoradiation therapy. This
may be because premalignant cells disseminate early during the malignant process and are not affected
by surgery, https://www.ncbi.nlm.nih.gov/pubmed/22265420 .
* Patients with locally advanced pancreatic cancer who have unresectable tumors because of local vessel
impingement or invasion by tumor may become candidates for radical pancreatic resection if
chemotherapy or chemoradiation therapy shrinks the tumor.
* Patients with locally advanced disease who are not surgical candidates may benefit from palliation of
biliary obstruction by endoscopic, surgical or radiological means.
Ablation and embolization
* Ablation and embolization treatments destroy tumors rather than removing them with surgery. To date,
the effectiveness is minimal to modest (https://pubmed.ncbi.nlm.nih.gov/34215498,
https://pubmed.ncbi.nlm.nih.gov/34163121, https://pubmed.ncbi.nlm.nih.gov/33807220).
Chemotherapy drugs based on cell growth
FOLFIRINOX: leucovorin [folinic acid, reduces side effects of 5-FU], 5-FU [inhibits DNA synthesis],
irinotecan [inhibits topoisomerase I] and oxaliplatin [inhibits DNA synthesis]
Gemcitabine (Gemzar) and capecitabine (Xeloda, oral 5-FU) [inhibit DNA synthesis]
S-1 for Japanese patients: tegafur [pro-drug of 5-FU], gimeracil [prevents breakdown of 5-FU], and
oteracil potassium [reduces GI toxicity of this therapy]
Gemcitabine and nab-paclitaxel [albumin bound paclitaxel to improve its distribution]
Irinotecan (Camptosar) or Liposomal Irinotecan (Onivyde) [inhibits topoisomerase I]
Taxanes: Paclitaxel (Taxol), Docetaxel (Taxotere), and Albumin-bound paclitaxel (Abraxane) [inhibit cell
division by interference with mitotic spindle formation]
Targeted therapy:
Erlotinib (Tarceva) is an anti-EGFR drug (acts on cell growth) given without molecular testing, often in
combination with gemcitabine, https://pubmed.ncbi.nlm.nih.gov/17452677
Olaparib (Lynparza) is a PARP inhibitor given to patients with germline BRCA mutations [inhibit DNA
repair], https://pubmed.ncbi.nlm.nih.gov/31157963
Larotrectinib (Vitrakvi) and entrectinib (Rozlytrek) target various tumors with NTRK gene fusions,
including 1% of pancreatic adenocarcinomas. These molecular changes are detected by next generation
sequencing (NGS), https://pubmed.ncbi.nlm.nih.gov/32755482
Pembrolizumab (Keytruda) is an immune system checkpoint inhibitor (inhibits PD-1, a T cell checkpoint
protein that promotes immune suppression) which damages tumors with a high level of microsatellite
instability (MSI-H) or changes in mismatch repair (MMR) genes, often seen in Lynch syndrome
2. Treatments not typically part of current protocols but worthy of further investigation
Metformin, particularly in patients with diabetes, https://pubmed.ncbi.nlm.nih.gov/32580502,
https://pubmed.ncbi.nlm.nih.gov/32925714
Treatments affecting the pancreatic tumor microenvironment:
Inflammation:
* Reduce inflammation by stimulating its resolution and inhibiting inflammatory biomarkers,
https://pubmed.ncbi.nlm.nih.gov/31205032 (mice),
https://pubmed.ncbi.nlm.nih.gov/29228980 (cell lines),
https://pubmed.ncbi.nlm.nih.gov/32891711 (general discussion)
* Vasculature, https://pubmed.ncbi.nlm.nih.gov/30889903,
https://pubmed.ncbi.nlm.nih.gov/33546207
* Stroma: fibroblasts, stellate cells; endothelial, neuronal, and immune cells; extracellular matrix
https://pubmed.ncbi.nlm.nih.gov/33546207, https://pubmed.ncbi.nlm.nih.gov/34336679
Early dissemination of tumor cells, https://pubmed.ncbi.nlm.nih.gov/22265420,
Using glucocoticoids: https://pubmed.ncbi.nlm.nih.gov/33115754,
https://pubmed.ncbi.nlm.nih.gov/32619553/, https://pubmed.ncbi.nlm.nih.gov/33519206,
https://pubmed.ncbi.nlm.nih.gov/32803553
Chronic inflammation, often low grade and associated with risk factors
https://pubmed.ncbi.nlm.nih.gov/32283655,
http://www.natpernick.com/ChronicInflammationpaperMay2020.html
Immune system dysfunction, https://pubmed.ncbi.nlm.nih.gov/32247999,
https://pubmed.ncbi.nlm.nih.gov/32457830, https://pubmed.ncbi.nlm.nih.gov/34103944
Germline changes promoting malignancy
● BRCA2, BRCA1, PALB2, CDKN2A, ATM, TP53 and mismatch repair genes MLH1, MSH2, MSH6
● Theoretically important but limited clinical trials on targeted therapy other than for BRCA,
https://pubmed.ncbi.nlm.nih.gov/29069866
● BRCA (4-7%): Olaparib improves progression free but not overall survival in metastatic disease,
https://pubmed.ncbi.nlm.nih.gov/31157963
Behavioral risk factors promoting malignancy, but limited clinical trials on how countering them affects
disease progression
● Excess weight: although a major risk factor, it is not typically considered a treatment because
weight loss is commonly associated with disease, https://pubmed.ncbi.nlm.nih.gov/30591550/
● Cigarette smoking
● Type 2 diabetes
● Excessive alcohol use
● Diet: integrated management may improve patient outcomes,
https://pubmed.ncbi.nlm.nih.gov/33114159, https://pubmed.ncbi.nlm.nih.gov/29478350/ ,
https://pubmed.ncbi.nlm.nih.gov/32821804 (breast cancer)
● Exercise: https://pubmed.ncbi.nlm.nih.gov/31562341,
https://pubmed.ncbi.nlm.nih.gov/33835957
Non behavioral risk factors promoting malignant change
● Non O blood group: https://pubmed.ncbi.nlm.nih.gov/32173688
● Family history
● Chronic pancreatitis
● Reflux due to variant anatomy of biliary system: https://pubmed.ncbi.nlm.nih.gov/32336556
● Random chronic stress / bad luck
3. Additional strategic considerations:
* Target dysfunctional cancer networks, not just mutations, which represents only one of many
alterations possible at each step in the targeted biologic pathway.
* Consider combinations of 3-5 drugs for each malignant attribute to adequately damage its biologic web.
* Since treatment typically does not kill all cancer cells, it is important to move surviving cancer cells into
less hazardous networks (Curing Cancer - Part 5 - Key network issues that affect the primary
tumor), termed communicative reprogramming or metabolic reprogramming.
* Monitor the status of systemic networks promoting the malignant process before and after treatment.
* Treatment should focus on managing the malignancy to reduce death and disability, not eliminating
every possible cancer cell.
* Aggressively enroll patients into clinical trials so physicians can learn and improve over time.
* Study and minimize deaths occurring shortly after diagnosis, which may be due to infections, treatment
side effects or marked derangements to essential physiologic systems (Curing Cancer Blog - Part 9,
Zaorsky 2017).
* Consider achieving “marginal gains” at all steps of the disease process, which may increase possible
treatment options and reduce a sense of futility which damages survival.
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