combination therapy Archives | Mikhail Blagosklonny Oncotarget

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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This article dissects Dr. Mikhail V. Blagosklonny’s paradigm-shifting perspective on preemptive combinations for treating EGFR-mutant non-small cell lung cancer.

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In the relentless battle against non-small cell lung cancer (NSCLC) driven by epidermal growth factor receptor (EGFR) mutations, the development of resistance has long been a formidable obstacle. Historically, first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) like gefitinib, erlotinib, afatinib, and dacomitinib have faced a significant hurdle: the emergence of the T790M point mutation in approximately 50% of patients, rendering the tumor resistant to these therapies.

This resistance stems from a sobering reality – before treatment, a small subset of cancer cells already harbor the T790M mutation, conferring no selective advantage initially. However, once treatment commences, these rare mutated cells proliferate selectively, eventually dominating the tumor population and diminishing the effectiveness of first- and second-generation TKIs.

The Rise of Osimertinib: A Beacon of Hope

In 2015, the FDA approved osimertinib, a third-generation EGFR TKI, as a second-line therapy for NSCLC patients with the T790M mutation. This approval recognized that untreated tumors are typically T790M-negative, with the mutation potentially present in only a single cell initially. Moreover, approximately 50% of patients do not harbor this mutation at all, underscoring the rationale for administering osimertinib after resistance to first- or second-generation TKIs emerges.

However, a paradigm shift was on the horizon. Osimertinib’s ability to target the T790M mutation, coupled with its potential to eliminate the rare resistant cells before they proliferate, paved the way for a groundbreaking approach: administering osimertinib as a first-line treatment, without waiting for resistance to develop.

Preemptive Combinations: A Multifaceted Strategy

In a seminal 2018 clinical trial, osimertinib demonstrated its prowess as a first-line treatment, significantly extending median progression-free survival (PFS) compared to first-generation EGFR inhibitors (18.9 months vs. 10.2 months). Remarkably, while the objective response rates were similar between the two groups, the duration of response was nearly doubled with osimertinib (17.2 months vs. 8.5 months).

Capitalizing on these findings, Dr. Mikhail V. Blagosklonny introduced the concept of “preemptive combinations” – a multi-pronged approach to not only induce a therapeutic response but also eliminate the few resistant cells harboring pre-existing mutations. By combining osimertinib with first- or second-generation EGFR inhibitors like gefitinib and afatinib, these preemptive combinations could potentially prevent on-target resistance mechanisms, thereby extending PFS and overall survival (OS) for a substantial proportion of patients. On March 15, 2024, Dr. Blagosklonny’s research perspective was published in Oncotarget’s Volume 15, entitled, “From osimertinib to preemptive combinations.”

Expanding the Armamentarium: Comprehensive Preemptive Combinations

While osimertinib addresses the T790M mutation, other resistance mechanisms remain a concern. Approximately 50% of resistance cases involve on-target secondary mutations within EGFR, such as L718, G724, L792, G796, and C797, which can be targeted by first- or second-generation EGFR inhibitors. Additionally, off-target mechanisms like MET and HER2 amplifications contribute to resistance.

To combat this multifaceted challenge, Dr. Blagosklonny proposed a comprehensive preemptive combination comprising osimertinib, afatinib (or a first-generation EGFR inhibitor), and capmatinib (a potent MET inhibitor). This triple-threat approach could potentially prevent up to 75% of resistance mechanisms, dramatically extending median PFS from 18 months with osimertinib alone to an estimated 40 months.

Addressing Heterogeneity: The Bittersweet Reality

While osimertinib undoubtedly improves median PFS and OS compared to first-generation TKIs, a sobering reality emerges: approximately 20% of patients may experience a shortened PFS due to pre-existing mutations like C797S, which render the tumor resistant to osimertinib but sensitive to first-generation TKIs. In these cases, osimertinib inadvertently selects for resistant clones, potentially harming a subset of patients.

The solution, as proposed by Dr. Blagosklonny, lies in the simplicity of preemptive combinations. By combining osimertinib with gefitinib, or even a triple combination with afatinib, the risk of selecting for resistant clones is mitigated, ensuring that no patient is inadvertently harmed by the superior TKI.

Transient Combinations: A Flexible Approach

For clinicians who may be hesitant about administering three- or four-drug combinations, Dr. Blagosklonny suggests a flexible approach: a sequence of transient two-drug combinations. This strategy involves alternating between different combinations, such as osimertinib and gefitinib, followed by osimertinib and afatinib, and so on, effectively covering all potential resistance mechanisms while maintaining a manageable treatment regimen.

Extending the Paradigm: MET-Driven NSCLC

The insights gleaned from EGFR-driven NSCLC can be applied to other molecular subtypes, such as MET exon 14 skipping mutation (METex14)-driven NSCLC. Dr. Blagosklonny’s personal experience with this condition underscores the importance of preemptive combinations in this setting as well.

While the selective MET inhibitor capmatinib demonstrated remarkable efficacy in treating Dr. Blagosklonny’s brain metastases, resistance tends to emerge within a year, often driven by secondary mutations like D1228 and Y1230. To combat this, a preemptive combination of capmatinib, afatinib (to target EGFR and HER2 alterations), and cabozantinib (a type II MET inhibitor effective against resistance mutations) could potentially prevent up to 50% of resistance mechanisms, prolonging progression-free survival for a significant proportion of METex14-driven NSCLC patients.

Overcoming Hurdles: The Path Forward

Despite the promise of preemptive combinations, challenges remain. The development of novel targeted therapies and the exploration of immune checkpoint inhibitors in combination with these regimens offer exciting avenues for future research. Additionally, refining clinical trial designs to incorporate precision medicine approaches and tailored combination strategies will be crucial in translating these concepts into tangible benefits for patients.

Conclusion: A Paradigm Shift in Cancer Care

Dr. Blagosklonny’s perspective on preemptive combinations represents a paradigm shift in the treatment of lung cancer and potentially other malignancies. By proactively targeting resistance mechanisms before they can take hold, this approach offers a glimmer of hope for prolonging progression-free survival and improving outcomes for patients grappling with this disease. As research continues to unravel the complexities of cancer resistance, preemptive combinations may pave the way for a future where we can stay one step ahead of cancer.

Click here to read the full research perspective in Oncotarget.

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Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).