Tagged: pancreatic cancer

Novel Triple-Drug Combination to Fight Pancreatic Cancer

July 25, 2024

In this new study, researchers unveiled a promising synergistic strategy for combating pancreatic cancer.

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In the ever-evolving quest for effective cancer treatments, researchers are continuously exploring innovative combinatorial approaches that exploit the vulnerabilities of malignant cells. In a new study, researchers Benigno C. Valdez, Apostolia M. Tsimberidou, Bin Yuan, Yago Nieto, Mehmet A. Baysal, Abhijit Chakraborty, Clark R. Andersen, and Borje S. Andersson from The University of Texas MD Anderson Cancer Center unveiled a promising synergistic strategy for combating pancreatic cancer (a cancer known for its resistance to conventional therapies). On June 3, 2024, their research paper was published in Oncotarget’s Volume 15, entitled, “Synergistic cytotoxicity of histone deacetylase and poly-ADP ribose polymerase inhibitors and decitabine in pancreatic cancer cells: Implications for novel therapy.”

The Role of HDACs in Cancer

By harnessing the collective power of decitabine, histone deacetylase inhibitors (HDACis), and poly(ADP-ribose) polymerase inhibitors (PARPis), a multifaceted approach has demonstrated remarkable cytotoxic effects against pancreatic cancer cells, offering hope for improved treatment outcomes. Recognizing the pivotal role of HDACs in cancer pathogenesis, researchers have developed HDAC inhibitors, which induce gene expression, triggering cell differentiation, cell cycle arrest, and apoptosis in cancer cells. These inhibitors, including vorinostat, romidepsin, panobinostat, and belinostat, have received regulatory approval for treating hematologic malignancies. While HDACis have shown promise in preclinical studies, their clinical efficacy as monotherapy is limited. However, when combined with other anticancer drugs, enhanced anti-tumor activity has been observed, sparking interest in exploring synergistic combinations.

Histone acetylation, a critical epigenetic modification, governs gene expression and is catalyzed by histone acetyltransferases. This process involves the acetylation of positively charged lysine residues on the N-terminal tails of histones, reducing their interactions with negatively charged DNA and resulting in a relaxed chromatin structure that facilitates increased transcriptional activation and gene expression. Conversely, histone deacetylases (HDACs) remove acetyl groups, leading to a condensed, transcriptionally inactive chromatin state. Dysregulation of HDACs is implicated in the downregulation of tumor suppressor genes, contributing to the development and progression of various malignancies, including pancreatic cancer.

The DNA Repair Conundrum: Exploiting PARP Inhibitors

Another key player in the battle against pancreatic cancer is the poly(ADP-ribose) polymerase (PARP) enzyme family. These enzymes catalyze the process of poly(ADP-ribosyl)ation (PARylation), which is crucial for DNA repair mechanisms. By binding to DNA breaks, PARP enzymes self-ribosylate and recruit DNA repair proteins, facilitating the restoration of genomic integrity. Recognizing the pivotal role of PARP in DNA repair, researchers have developed potent PARP inhibitors (PARPis), such as olaparib and talazoparib. These agents have demonstrated remarkable efficacy in patients with metastatic pancreatic adenocarcinoma harboring BRCA1/2 germline mutations, which impair homologous recombination repair (HRR) pathways.

Decitabine, a nucleoside cytidine analogue, has emerged as a potent ally in the fight against pancreatic cancer. When phosphorylated, decitabine is incorporated into the growing DNA strand, inhibiting methylation and inducing DNA damage by inactivating and trapping DNA methyltransferase on the DNA. This process activates transcriptionally silenced DNA loci, potentially sensitizing cancer cells to other therapeutic interventions. Interestingly, decitabine has been associated with sensitivity in patients with KRAS-mutated pancreatic cancer, a prevalent genetic alteration in this malignancy.

The Synergistic Triad: Decitabine, HDACis, & PARPis Unite

In the current study, the researchers explored various combinations of HDACis (panobinostat and vorinostat), PARPis (talazoparib and olaparib), and decitabine in pancreatic cancer cell lines. The findings were nothing short of remarkable. The combination of HDACis and PARPis resulted in synergistic cytotoxicity across all tested cell lines, including those harboring wild-type BRCA1/2 (BxPC-3 and PL45) and a BRCA2 mutation (Capan-1).

The addition of decitabine further amplified the synergistic cytotoxicity observed with HDACis and PARPis, triggering increased apoptosis, as evidenced by elevated cleavage of caspase 3 and PARP1. Moreover, the triple-drug combinations induced heightened DNA damage, as demonstrated by increased phosphorylation of histone 2AX. The synergistic combinations disrupted various DNA repair pathways, as indicated by decreased levels of key proteins involved in the DNA damage response, such as ATM, BRCA1, and ATRX.

Remarkably, the triple-drug combinations altered the epigenetic regulation of gene expression by reducing the levels of subunits of the nucleosome remodeling and deacetylase (NuRD) complex, a crucial regulator of chromatin remodeling and deacetylation processes.

Mechanistic Insights & Clinical Implications

The synergistic cytotoxicity observed in this study can be attributed to the collective impact of HDACis, PARPis, and decitabine on various cellular processes. HDACis modulate the acetylation status of proteins, influencing genomic instability and potentially sensitizing cancer cells to DNA-damaging agents. Concurrently, PARPis inhibit protein PARylation, a critical process in DNA repair mechanisms. The addition of decitabine potentiates these effects by inducing DNA damage and activating transcriptionally silenced DNA loci. This multifaceted approach effectively disrupts DNA repair pathways, triggers apoptosis, and modulates epigenetic regulation, collectively amplifying cytotoxic effects against pancreatic cancer cells.

The findings of this study hold significant clinical implications for treating pancreatic cancer, a malignancy with a dismal prognosis and limited therapeutic options. By leveraging the synergistic interactions between HDACis, PARPis, and decitabine, this novel combinatorial approach has the potential to improve treatment outcomes and prolong survival for patients with this aggressive disease. The study provides a strong rationale for further exploration of these combinations in clinical trials, potentially leading to personalized therapeutic strategies tailored to individual patient profiles and tumor characteristics. However, additional preclinical investigations and rigorous clinical trials are necessary to validate these findings and address potential challenges, such as drug toxicities and pharmacodynamic interactions. By embracing a collaborative and multidisciplinary approach, the scientific community can transform these discoveries into tangible clinical benefits, advancing cancer care and offering hope to those battling this formidable disease.

Click here to read the full research paper in Oncotarget.

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Oncotarget is an open-access, peer-reviewed journal that publishes primarily oncology-focused research papers. These papers are available to readers (at no cost and free of subscription barriers) in a continuous publishing format at Oncotarget.com.

Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative), and Dimensions (Digital Science).

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Immunotherapy Response in Primary vs Metastatic Pancreatic Cancer

November 16, 2023

In this editorial, researchers delve into the immunotherapeutic challenges posed by the tumor microenvironment and liver metastasis in pancreatic cancer.

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Pancreatic ductal adenocarcinoma (PDA), a common type of pancreatic cancer, has proven to be largely resistant to immunotherapy, a treatment that uses the body’s immune system to fight cancer. Despite numerous successful pre-clinical trials using sophisticated PDA mouse models, clinical trials have failed to show a significant improvement in survival.

In a recent editorial, researchers Brian Diskin, Sarah Schwartz and George Miller from Trinity Health of New England shed light on the complex interplay between the immune system and pancreatic cancer. Their paper was published in Oncotarget on April 24, 2023, and entitled, “The critical immune basis for differential responses to immunotherapy in primary versus metastatic pancreatic cancer.”

Tumor Microenvironment and Liver Metastasis: Challenges in Pancreatic Cancer

The authors attribute PDA immunotherapy resistance to the unique characteristics of the tumor microenvironment (TME). The TME is often hypoxic and fibrotic, making it inaccessible to immune cells. Furthermore, the immune cells that do infiltrate the TME often have tolerogenic features, meaning they are more likely to tolerate the presence of cancer cells rather than attack them.

PDA most commonly metastasizes to the liver, an organ known for its immune tolerance. The liver is home to a diverse array of innate immune populations, including NK cells, Kupfer cells, NKT cells, and double negative T cells. Despite this, the liver is the most common location for metastasis from gastrointestinal cancers.

“It is an unfortunate fact that all failed clinical trials assessing immunotherapeutic efficacy were conducted in metastatic PDA, whereas basic preclinical investigations are usually performed in primary PDA using genetically engineered mouse models. We postulated that this dichotomy may explain the gap between preclinical promise and ultimate clinical failure.”

Divergent Responses to Immunotherapy: Primary vs. Metastatic

“The potentially divergent responses to immunotherapy in the respective environments of primary versus metastatic PDA within the same host has not been well-studied.”

The authors highlight the lack of research into the potentially divergent responses to immunotherapy in primary versus metastatic PDA. They argue that this gap in knowledge may explain the discrepancy between the promising results of pre-clinical trials and the disappointing outcomes of clinical trials.

In their research, they discovered that the TMEs of primary PDA and liver metastases differ significantly, and this difference plays a critical role in the site-specific response to immunotherapy. They found that liver metastases are uniquely resistant to immunotherapies, in stark contrast to the immunotherapeutic responsiveness of primary PDA.

“We discovered that the respective TMEs of primary PDA and liver metastases differ markedly and this fact plays a critical role in dictating site-specific PDA response to immunotherapy [6].”

The Role of B Cells

The researchers identified B cells as a key player in this differential response. They found that B cells constituted approximately 25% of the tumor-infiltrating lymphocytes in metastatic PDA liver deposits, compared to approximately 10% in primary PDA. They also discovered a novel population of CD24+CD44–CD40– B cells in the metastatic liver, which is recruited to the metastatic milieu by Muc1hiIL18hi tumor cells.

“[…] by targeting B cells or blocking CD200/BTLA, we demonstrated enhanced macrophage and T-cell immunogenicity, which enabled immunotherapeutic efficacy of liver metastases.”

However, the authors note that primary PDA sites lack this b-cell population. Instead, they are characterized by macrophages and effector T cells that have a higher ability to provoke an immune response. This makes their immunotherapeutic responsiveness far more robust than metastatic liver PDA.

Conclusion

This research underscores the importance of understanding the immune basis of differential responses to immunotherapy in primary versus metastatic pancreatic cancer. It highlights the need for further research into the role of the TME and immune cells like B cells in the response to immunotherapy. Such insights could pave the way for more effective treatments for this challenging disease.

“[…] our data suggest that models of primary PDA are poor surrogates for evaluating immunity or treatment response in advanced disease.”

Click here to read the full editorial paper in Oncotarget.

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Oncotarget is an open-access, peer-reviewed journal that has published primarily oncology-focused research papers since 2010. These papers are available to readers (at no cost and free of subscription barriers) in a continuous publishing format at Oncotarget.com. Oncotarget is indexed/archived on MEDLINE / PMC / PubMed.

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Oncotarget

Controlling Glycolytic Flux: Therapy Challenges and Solutions

February 16, 2023

In a new editorial paper, researchers from the University of Oxford explore challenges and potential solutions for controlling glycolytic flux by blocking lactate transporters in disease therapies.

Targeting Lactate Transporters for Disease Therapies

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Listen to an audio version of this article

The process of glycolysis, or the conversion of glucose to energy in cells, is a critical component of many biological processes. This process is highly regulated, and glycolytic flux has been implicated in a variety of disease states, including cancer and diabetes. Despite significant advances in our understanding of glycolysis, researchers continue to find it difficult to control glycolytic flux.

“Overall, glycolysis facilitates tumour proliferation and survival, and has become a hotly-pursued target for therapeutic inhibition.”

In a new editorial paper, researchers Wiktoria Blaszczak and Pawel Swietach from the University of Oxford explored the challenges of this issue and potential solutions. On January 26, 2023, their editorial was published in Oncotarget and entitled, “Permeability and driving force: why is it difficult to control glycolytic flux by blocking lactate transporters?“

“In our recent study (Blaszczak et al. (2022)), using a panel of pancreatic ductal adenocarcinoma cell lines, we characterised how extracellular acidity feeds back to inhibit further glycolytic acid production [6].”

Blocking Lactate Transporters: Challenges

Lactate is produced as a byproduct of glycolysis. Lactate transporters are responsible for moving lactate out of cells. Blocking these transporters has long been thought of as a potential way to slow or stop glycolytic flux. However, as the authors of this editorial point out, attempts to do so have been met with limited success.

One of the key challenges in blocking lactate transporters is their complex regulation. These transporters are highly permeable to lactate, meaning that even small changes in their activity can have a significant impact on lactate flux. Additionally, lactate transporters are regulated by a variety of factors, including pH, ion concentrations and intracellular signaling pathways. This complexity makes it difficult to design drugs that selectively target lactate transporters without affecting other cellular processes.

Another challenge in blocking lactate transporters is the driving force that fuels lactate transport. The movement of lactate out of cells is driven by a concentration gradient, meaning that lactate moves from areas of high concentration to areas of low concentration. However, this gradient is often very small, meaning that even small changes in the activity of lactate transporters can have a significant impact on lactate flux. Additionally, lactate transporters are often coupled with other transporters, such as H+ transporters, which can further complicate efforts to block lactate transport.

Blocking Lactate Transporters: Solutions

Despite these challenges, the authors suggest that there may be ways to overcome them and better control glycolytic flux by targeting lactate transporters. One potential approach is to develop drugs that selectively target lactate transporters and are not affected by other cellular processes. This could be achieved by exploiting the structural differences between lactate transporters and other transporters. Additionally, targeting the intracellular signaling pathways that regulate lactate transporters could be a way to more selectively block lactate transport.

Another potential approach to controlling glycolytic flux is to target the driving force that fuels lactate transport. This could be achieved by altering the concentration gradient of lactate, either by blocking lactate production or by increasing lactate consumption. Additionally, targeting other transporters that are coupled with lactate transporters, such as H+ transporters, could be a way to indirectly control lactate transport and glycolytic flux.

“Overall, a decrease in permeability will increase driving force, thereby restoring flux.”

Conclusion

Overall, the researchers highlight the complex nature of lactate transport and the challenges that must be overcome to control glycolytic flux by blocking lactate transporters. Additionally, the authors suggest that there are potential solutions to these challenges and that continued research could lead to new insights into the regulation of glycolysis and the development of new therapies for diseases associated with alterations in glycolytic flux.

“Regardless of the chosen approach, it is likely that any successful therapeutic strategy for targeting glycolysis will be multifaceted to overcome some of the intricacies of complex pathways.”

Click here to read the full editorial published in Oncotarget.

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