As an overview of Pancreatic Neuroendocrine Tumors, we look at the current standard treatment for pNETs and what emerging therapies are on the horizon. Also discussed is the translational research needed to increase the success of current and emerging therapies.
How are pNETs treated and what emerging therapies are being explored?
For some small, low-grade, nonfunctioning pNETs with no evidence of metastasis, a conservative “watchful waiting” strategy may be adopted, involving regular monitoring in lieu of immediate surgery. In some cases, these tumors may never progress to become symptomatic or require intervention.
Surgery
pNETs are frequently localized, low-grade and slow-growing; therefore, surgery is the most common treatment, as complete removal of the tumor can be curative. The specific surgical approach depends on tumor size and location, and whether it is functional or nonfunctional. The goal of surgery is to remove all tumor tissue while preserving as much healthy normal pancreas tissue as possible. For larger or more complex tumors, partial or total removal of the pancreas may be necessary, which can result in the development of diabetes.
For slow growing functional pNETs, excess hormone production is often the main cause of symptoms. In these cases, rather than completely removing the tumor, a debulking procedure may be performed to eliminate enough tissue to reduce hormone production and reduce symptoms while avoiding total tumor removal.
Since surgery for pancreatic tumors (PDAC or pNET) can damage surrounding healthy tissue, it can leave patients with diabetes or deficiencies in pancreatic enzymes following the procedure. As a result, less invasive methods for tumor removal or destruction are being explored as alternative strategies for managing pNET. These include:
EUS guided probe generates high temperatures using radio waves and induces localized tissue injury, causing cell death.
EUS guided needle injects an alcohol solution into the tumor to kill tumor cells.
Therapies for Advanced or High-Grade pNETs
For low grade tumors that have spread to other organs or for high grade tumors, surgery is not an option. The following therapies are approved and commonly used for these patients.
SSAs such as octreotide and lanreotide bind somatostatin receptors, inhibiting a key survival pathway.
SSAs connected to radioactive compounds (177Lu-DOTATATE) to deliver radiation only to cells that express somatostatin receptors. An emerging type of radiotherapy, Targeted Alpha Therapy (TAT) is being tested in clinical trials and may offer less off-target radiation effects thereby increasing safety.
Drugs that block key signaling pathways that fuel tumor growth or survival. Approved therapies include everolimus (mTOR signaling), sunitinib (multiple pathways), and belxutifan (HIF-2ɑ signaling in VHL patients). Additional inhibitors targeting related or overlapping pathways are also being investigated in pNETs to better determine which pathways are most critical for tumor growth and to identify therapeutic combinations that may provide the most effective tumor control.
Used in patients with metastatic or high-grade tumors. Commonly used chemotherapies include streptozocin, 5-fluoruracil (5-FU), doxorubicin, capecitabine, and temozolomide.
Combinations of these separate therapies are currently being tested in the clinic to find optimal treatment regimens that increase responses and survival without decreasing quality of life.
Emerging Therapy: Antibody-Drug Conjugates
Antibody-Drug Conjugates (ADCs)
A novel class of drugs that offer the potential to deliver chemotherapy selectively to tumor cells. ADCs use antibodies that recognize proteins specifically expressed on tumor cells to carry and release highly potent drugs directly at the tumor site, minimizing damage to healthy tissue.
These therapies have shown promising results in leukemias and lymphomas, breast cancer, bladder cancer, and lung cancer. A key factor in their success is the identification of tumor-specific surface proteins. One such protein, DLL3, is expressed on pNETs — early studies demonstrated clinical activity, although significant side effects were observed.
Additional ADCs targeting tumor-associated proteins are currently in development and clinical testing across several cancers, including PDACs and pNETs. Continued translational research is still needed to identify additional pNET-specific targets that could accelerate the development of this promising therapeutic approach.
The Importance of Translational Research
Translational studies that analyze patient samples before and after treatment are critical for identifying biomarkers of response and understanding the tumor characteristics that determine sensitivity to specific therapies. Insights from these studies will help clinicians design more personalized treatment strategies tailored to the unique features of each patient’s tumor.
Hirshberg Foundation pNET Pathways Grant Program
Through the Hirshberg Foundation pNET Pathways Grant Program, we aim to accelerate research toward new therapeutic options for pNETs, helping ensure that all individuals affected by pancreatic diseases have greater hope for improved outcomes in the future.
