Sequential bortezomib and temozolomide treatment promotes immunological responses in glioblastoma patients with positive clinical outcomes: A phase 1B study

Rahman, Mohummad Aminur; Brekke, Jorunn; Arnesen, Victoria Smith; Hannisdal, Marianne H; Navarro, Andrea Gras; Waha, Andreas; Herfindal, Lars; Rygh, Cecilie Brekke; Bratland, Eirik; Brandal, Petter; Haász, Judit; Oltedal, Leif; Miletić, Hrvoje; Lundervold, Arvid; Lie, Stein Atle; Goplen, Dorota; Chekenya, Martha

doi:10.1002/iid3.315

Cited by 22 publications

(17 citation statements)

References 55 publications

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“…Like Ixazomib, Bortezomib (BTZ, Velcade) reversibly blocks the chymotryptic-like activity of the β1 and β5 subunits of the 26S proteasome. BTZ is approved for the treatment of multiple myeloma and mantle cell lymphoma ( Stapnes et al, 2007 ) and has been explored in early phase clinical studies for GBM ( Kubicek et al, 2009 ; Friday et al, 2012 ; Bota et al, 2013 ; Kong et al, 2018 ; Rahman et al, 2020 ). In vitro studies with BTZ alone or in combination with other drugs showed potent anti-cancer activity against various malignancies through multiple mechanisms ( Frankel et al, 2000 ; Nawrocki et al, 2002 ).…”

Section: Introductionmentioning

confidence: 99%

Bortezomib abrogates temozolomide-induced autophagic flux through an ATG5 dependent pathway

Rahman

Engelsen²,

Sarowar³

et al. 2022

Front. Cell Dev. Biol.

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Introduction: Glioblastoma (GBM) is invariably resistant to temozolomide (TMZ) chemotherapy. Inhibiting the proteasomal pathway is an emerging strategy to accumulate damaged proteins and inhibit their lysosomal degradation. We hypothesized that pre-treatment of glioblastoma with bortezomib (BTZ) might sensitize glioblastoma to temozolomide by abolishing autophagy survival signals to augment DNA damage and apoptosis.Methods: P3 patient-derived glioblastoma cells, as well as the tumour cell lines U87, HF66, A172, and T98G were investigated for clonogenic survival after single or combined treatment with temozolomide and bortezomib in vitro. We investigated the requirement of functional autophagy machinery by utilizing pharmacological inhibitors or CRISPR-Cas9 knockout (KO) of autophagy-related genes -5 and -7 (ATG5 and ATG7) in glioblastoma cells and monitored changes in autophagic flux after temozolomide and/or bortezomib treatments. P3 wild-type and P3 ATG5−/− (ATG5 KO) cells were implanted orthotopically into NOD-SCID mice to assess the efficacy of bortezomib and temozolomide combination therapy with and without functional autophagy machinery.Results: The chemo-resistant glioblastoma cells increased autophagic flux during temozolomide treatment as indicated by increased degradation of long-lived proteins, diminished expression of autophagy markers LC3A/B-II and p62 (SQSTM1), increased co-localisation of LC3A/B-II with STX17, augmented and no induction of apoptosis. In contrast, bortezomib treatment abrogated autophagic flux indicated by the accumulation of LC3A/B-II and p62 (SQSTM1) positive autophagosomes that did not fuse with lysosomes and thus reduced the degradation of long-lived proteins. Bortezomib synergistically enhanced temozolomide efficacy by attenuating cell proliferation, increased DNA double-strand breaks, and apoptosis in an autophagy-dependent manner. Abolishing autophagy in ATG5 KOs reversed the bortezomib-induced toxicity, rescued glioblastoma cell death and reduced animal survival.Discussion: We conclude that bortezomib abrogates temozolomide induced autophagy flux through an ATG5 dependent pathway.

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Section: Introductionmentioning

confidence: 99%

Bortezomib abrogates temozolomide-induced autophagic flux through an ATG5 dependent pathway

Rahman

Engelsen²,

Sarowar³

et al. 2022

Front. Cell Dev. Biol.

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“…P3 cells were previously generated from the low passage of patient-derived xenografts and were stabilized as a stem-like cell line (characterized by IDH1 wt and MGMT unmethylated promoter [ 15 ]). Patient-derived glioblastoma cells P3 were cultured in neurobasal medium (NBM) supplemented with B-27 serum-free supplement (ThermoFisher Scientific), heparin (100 U/µL), penicillin/streptomycin (1000 U/mL) and basic FGF-2 20 ng/mL, in a 37 °C and 5% CO 2 incubator.…”

Section: Methodsmentioning

confidence: 99%

Refining the Role of Pyruvate Dehydrogenase Kinases in Glioblastoma Development

Larrieu

Storevik

Guyon

et al. 2022

Cancers

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Glioblastoma (GB) are the most frequent brain cancers. Aggressive growth and limited treatment options induce a median survival of 12–15 months. In addition to highly proliferative and invasive properties, GB cells show cancer-associated metabolic characteristics such as increased aerobic glycolysis. Pyruvate dehydrogenase (PDH) is a key enzyme complex at the crossroads between lactic fermentation and oxidative pathways, finely regulated by PDH kinases (PDHKs). PDHKs are often overexpressed in cancer cells to facilitate high glycolytic flux. We hypothesized that targeting PDHKs, by disturbing cancer metabolic homeostasis, would alter GB progression and render cells vulnerable to additional cancer treatment. Using patient databases, distinct expression patterns of PDHK1 and PDHK2 in GB tissues were obvious. To disturb protumoral glycolysis, we modulated PDH activity through the genetic or pharmacological inhibition of PDHK in patient-derived stem-like spheroids. Striking effects of PDHKs inhibition using dichloroacetate were observed in vitro on cell morphology and metabolism, resulting in increased intracellular ROS levels and decreased proliferation and invasion. In vivo findings confirmed a reduction in tumor size and better survival of mice implanted with PDHK1 and PDHK2 knockout cells. Adding a radiotherapeutic protocol further resulted in a reduction in tumor size and improved mouse survival in our model.

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“…The results suggest that the addition of Bortezomib into the current radiochemotherapy for patients with newly diagnosed GBM was well tolerated, and the PFS and OS rates show more promising values, especially in patients with the MGMT gene promoter methylation [ 97 ]. A more recent report shows that a well-tolerated sequential treatment using Bortezomib plus TMZ promotes Th1-driven immunological responses in a group of patients showing better clinical outcomes [ 98 ].…”

Section: Novel Therapeutic Strategies For Gbmmentioning

confidence: 99%

Adjusting the Molecular Clock: The Importance of Circadian Rhythms in the Development of Glioblastomas and Its Intervention as a Therapeutic Strategy

Wagner

Prucca

Caputto

et al. 2021

IJMS

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Gliomas are solid tumors of the central nervous system (CNS) that originated from different glial cells. The World Health Organization (WHO) classifies these tumors into four groups (I–IV) with increasing malignancy. Glioblastoma (GBM) is the most common and aggressive type of brain tumor classified as grade IV. GBMs are resistant to conventional therapies with poor prognosis after diagnosis even when the Stupp protocol that combines surgery and radiochemotherapy is applied. Nowadays, few novel therapeutic strategies have been used to improve GBM treatment, looking for higher efficiency and lower side effects, but with relatively modest results. The circadian timing system temporally organizes the physiology and behavior of most organisms and daily regulates several cellular processes in organs, tissues, and even in individual cells, including tumor cells. The potentiality of the function of the circadian clock on cancer cells modulation as a new target for novel treatments with a chronobiological basis offers a different challenge that needs to be considered in further detail. The present review will discuss state of the art regarding GBM biology, the role of the circadian clock in tumor progression, and new chrono-chemotherapeutic strategies applied for GBM treatment.

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Sequential bortezomib and temozolomide treatment promotes immunological responses in glioblastoma patients with positive clinical outcomes: A phase 1B study

Cited by 22 publications

References 55 publications

Bortezomib abrogates temozolomide-induced autophagic flux through an ATG5 dependent pathway

Bortezomib abrogates temozolomide-induced autophagic flux through an ATG5 dependent pathway

Refining the Role of Pyruvate Dehydrogenase Kinases in Glioblastoma Development

Adjusting the Molecular Clock: The Importance of Circadian Rhythms in the Development of Glioblastomas and Its Intervention as a Therapeutic Strategy

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