Studies identify novel PDAC therapeutic target

Two recent studies have independently identified macropinocytosis, a nutrient procurement pathway whereby cancer cells take up extracellular fluid droplets containing proteins and other macromolecules, as a promising new therapeutic target for pancreatic ductal adenocarcinoma (PDAC).

PDAC is one of the deadliest cancers, is often diagnosed late and has a poor 5-year survival, according to the American Cancer Society. Moreover, its incidence is increasing, with PDAC being predicted to become the second-leading cause of cancer-related deaths in the U.S. by 2030.

In a study reported in the March 2, 2021, edition of Cancer Discovery, scientists at Sanford Burnham Prebys Medical Discovery Institute (SBPI) in La Jolla, California, showed that blocking macropinocytosis slowed tumor growth, suggesting macropinocytosis drives PDAC growth and is an important new therapeutic target.

"Now that we know that macropinocytosis is [accelerated] in both pancreatic cancer cells and the surrounding fibrotic tissue, blocking the process might provide a double [blow] to pancreatic tumors," said senior author Cosimo Commisso, an associate professor and co-director of the Cell and Molecular Biology of Cancer Program at SBPI in a press release.

"We are investigating several drug candidates that inhibit macropinocytosis, and this study [shows] that they should be advanced as quickly as possible," said Commisso.

PDACs are surrounded by an unusually thick stromal layer, which makes it difficult for treatments to access the tumor, and fuels tumor growth by providing the tumor with nutrients.

Commisso's previous research had shown that rapidly growing PDACs obtain nutrients via macropinocytosis, an alternative nutritional route, indicating that stromal macropinocytosis may also fuel tumor growth.

To test this, the researchers blocked macropinocytosis in the cancer-associated fibroblasts (CAFs) that surround and nourish tumors, then co-transplanted the modified cells with pancreatic tumor cells into mice.

Compared to untreated controls, tumor growth was slowed in the transplanted mice, suggesting that blocking macropinocytosis is a promising way to treat PDAC.

"Instead of removing the stroma, which can cause the tumor to spread throughout the body, we simply block the process that is driving tumor growth," said study first author Yijuan Zhang, a postdoctoral researcher in Commisso's laboratory.

"We also deciphered the molecular signals that drive macropinocytosis in the stroma, providing new therapeutic avenues for pancreatic cancer researchers to explore."

Based on their ongoing macropinocytosis research, the SPBI researchers have now identified various druggable targets that may inhibit macropinocytosis and will continue to investigate drug candidates that inhibit macropinocytosis as potential new PDAC treatments, including as combination therapy.

Combination therapy

PDAC can also be treated by combining macropinocytosis inhibition with therapeutic autophagy, which maintains cellular homeostasis and suppresses tumorigenesis, according to a study reported in the March 16, 2021, online edition of Cancer Cell.

In established cancers, autophagy is also upregulated to support their high metabolic rates and energy demands by releasing amino acids and other components from lysosomally degraded macromolecules.

This apparent paradox suggests that autophagy inhibition should cause tumor starvation and regression.

However, studies of chloroquine and hydroxychloroquine, which disrupt lysosomal acidification and show anticancer activity in mice, did not show improved overall patient survival when combined with conventional chemotherapy.

Moreover, specific blockade of autophagy initiation is also ineffective, unless it is combined with ERK or MEK intracellular signaling inhibition.

Nevertheless, therapeutic autophagy inhibition has been of particular interest in treating PDACs, the majority of which are normally only detected at an advanced metastatic stage.

PDACs express high levels of autophagy and lysosome biosynthesis genes and correlate with MIT/TFE transcription factor protein upregulation.

These findings suggest that uninterrupted autophagy promotes PDAC growth and survival, which has indeed been previously established in mouse models.

PDACs are usually initiated by KRAS oncogenic mutations and harbor several other dominant genetic alterations. Moreover, oncogenic KRAS signaling to phosphatidylinositol 3-kinase (PI3K) post-translationally has been shown to activate the macropinocytosis cellular nutrient procurement pathway.

Like autophagy, macropinocytosis is a lysosome-dependent degradation pathway, but the mechanism whereby any macropinocytosis-enabled organism, including cancer cells, regulates autophagy and macropinocytosis is not fully understood.

In the new Cancer Cell study, researchers led by Michael Karin, a professor of pharmacology and pathology at the University of California San Diego School of Medicine in La Jolla, showed that autophagy blockade prompted established PDACs to upregulate and utilize macropinocytosis, allowing tumor cells to extract nutrients from extracellular sources.

The autophagy to macropinocytosis switch, which is not restricted to cancer cells, was shown to depend on activation of the nuclear transcription factor erythroid 2-related factor (NRF2) by the autophagy adaptor p62/SQSTM1 protein.

NRF2 activation by oncogenic mutations, hypoxia, and oxidative stress was also shown to result in macropinocytosis upregulation.

Moreover, inhibition of macropinocytosis in autophagy-compromised PDAC was shown to be associated with a dramatic metabolic decline and robust tumor regression.

Taken together, the findings of the two studies not only identify macropinocytosis as a promising therapeutic target for PDAC, but also indicate the therapeutic promise of combining autophagy and macropinocytosis inhibitors in treating the aggressive malignancy.

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