Exploration of Targeted Anti-tumor Therapy

Open Access

Original Article

The effect of iron on the expression levels of calcium related gene in cisplatin resistant epithelial ovarian cancer cells

Aim: Anticancer drugs (chemotherapeutics) used in cancer treatment (chemotherapy) lead to drug resistance. This study was conducted to investigate the possible effect of iron on calcium homeostasis [...] Read more.

Bahire Kucukkaya ... Leman Yalcintepe

Published: August 30, 2021 Explor Target Antitumor Ther. 2021;2:309–322
DOI: https://doi.org/10.37349/etat.2021.00048

Full Text

PDF

Download:39

Times Cited: 0

Open Access

Review

The promising potential of piperlongumine as an emerging therapeutics for cancer

In spite of the immense advancement in the diagnostic and treatment modalities, cancer continues to be one of the leading causes of mortality across the globe, responsible for the death of around 10 [...] Read more.

Dey Parama ... Ajaikumar B. Kunnumakkara

Published: August 30, 2021 Explor Target Antitumor Ther. 2021;2:323–354
DOI: https://doi.org/10.37349/etat.2021.00049

Full Text

PDF

Download:172

Times Cited: 8

Open Access

Review

The evolving role and utility of off-label drug use in multiple myeloma

The treatment landscape for multiple myeloma (MM) has dramatically changed over the last three decades, moving from no US Food and Drug Administration approvals and two active drug classes to over 1 [...] Read more.

James H Stoeckle ... Gareth J Morgan

Published: August 30, 2021 Explor Target Antitumor Ther. 2021;2:355–373
DOI: https://doi.org/10.37349/etat.2021.00050
This article belongs to the special issue Off-Label Drugs and -Omics Data in Cancer Treatment

Full Text

PDF

Download:46

Times Cited: 1

Open Access

Review

Does the gut microbiome environment influence response to systemic breast cancer treatment?

The gut microbiome is a novel player in the pathogenesis and treatment of breast cancer. The term “microbiome” is used to describe the diverse community of micro-organisms exis [...] Read more.

Eilidh Bruce ... Beatrix Elsberger

Published: August 30, 2021 Explor Target Antitumor Ther. 2021;2:374–384
DOI: https://doi.org/10.37349/etat.2021.00051

Full Text

PDF

Download:62

Times Cited: 3

Open Access

Review

Role of estrogen receptor coregulators in endocrine resistant breast cancer

Breast cancer (BC) is the most ubiquitous cancer in women. Approximately 70–80% of BC diagnoses are positive for estrogen receptor (ER) alpha (ERα). The steroid ho [...] Read more.

Kristin A. Altwegg, Ratna K. Vadlamudi

Published: August 30, 2021 Explor Target Antitumor Ther. 2021;2:385–400
DOI: https://doi.org/10.37349/etat.2021.00052
This article belongs to the special issue Endocrine Resistant Breast Cancer

Full Text

PDF

Download:103

Times Cited: 12

Open Access

Review

A novel strategy for treating cancer: understanding the role of Ca²⁺ signaling from nociceptive TRP channels in regulating cancer progression

Cancer is an aging-associated disease and caused by genomic instability that is driven by the accumulation of mutations and epimutations in the aging process. Although Ca2+ signaling, re [...] Read more.

Wen-Li Hsu ... Etsuro Ito

Published: October 31, 2021 Explor Target Antitumor Ther. 2021;2:401–415
DOI: https://doi.org/10.37349/etat.2021.00053
This article belongs to the special issue Calcium Signaling Apparatus in Cancers

Full Text

PDF

Download:70

Times Cited: 1

Open Access

Review

Current options and future directions of systemic therapy for advanced biliary tract cancer

Biliary tract cancers (BTCs) are aggressive tumors arising from different portions of the biliary tree and classified according to the anatomical location in intrahepatic (i) cholangiocarcinoma (CCA [...] Read more.

Maria Giuseppina Prete ... Lorenza Rimassa

Published: October 31, 2021 Explor Target Antitumor Ther. 2021;2:416–433
DOI: https://doi.org/10.37349/etat.2021.00054
This article belongs to the special issue Precision Medicine for Cholangiocarcinoma

Full Text

PDF

Download:81

Times Cited: 1

Open Access

Review

Targeting protein kinase CK2 in the treatment of cholangiocarcinoma

Cholangiocarcinoma (CCA) is a disease with a very poor prognosis and limited treatment options. Although targeted therapies directed towards specific mutations found in CCA are becoming available an [...] Read more.

Padma-Sheela Jayaraman, Kevin Gaston

Published: October 31, 2021 Explor Target Antitumor Ther. 2021;2:434–447
DOI: https://doi.org/10.37349/etat.2021.00055
This article belongs to the special issue Precision Medicine for Cholangiocarcinoma

Full Text

PDF

Download:69

Times Cited: 2

Open Access

Review

A review of molecularly targeted therapy in biliary tract carcinoma: what is the next step?

Patients with unresectable biliary tract carcinomas (BTCs) have a poor prognosis with a median overall survival of fewer than 12 months following systemic chemotherapy. In recent years, the identifi [...] Read more.

Patients with unresectable biliary tract carcinomas (BTCs) have a poor prognosis with a median overall survival of fewer than 12 months following systemic chemotherapy. In recent years, the identification of distinct molecular alterations with corresponding targeted therapies is modifying this therapeutic algorithm. The aim of this review is to present an overview of targeted therapy for BTCs, describing published available data and potential future challenges in ongoing trials. From clinicaltrials.gov online database all ongoing trials for BTCs (any stage) was examinated in July 2021, and data regarding study design, disease characteristics and type of treatments were registered. Oncogenic-driven therapy (targeted therapy) was investigated in 67 trials. According to research, 15 ongoing trials (22.4%) are investigating fibroblast growth factor (FGF) receptor (FGFR)-inhibitors in BTCs. Three (18.7%) are open-label randomized multicenter phase 3 trials, 8 (50%) are single-arm phase two trials, and 4 (25%) are phase one studies. Twelve (17.9%) clinical trials dealt with isocitrate dehydrogenase (IDH) 1/2 targeting therapy either in combination with cisplatin (Cis) and gemcitabine (Gem) as first-line treatment for BTCs or in monotherapy in patients with IDH1 mutant advanced malignancies, including cholangiocarcinoma (CCA). Nine (13.4%) clinical trials tested human epidermal growth factor receptor (HER) 2 targeting therapy. Four (44.4%) studies are phase I trials, two (22.2%) are phase I/II trials, and three (33.3%) phase II trials. Rare molecular alterations in BTCs, such as anaplastic lymphoma kinase (ALK), c-ros oncogene1 receptor tyrosine kinase (ROS1), and v-RAF murine sarcoma viral oncogene homologue B1 (BRAF), are also under investigation in a few trials. Forty-four clinical trials (17.2%) are investigating not oncogenic-driven multitarget therapy like multireceptor tyrosin kinase inhibitors and antiangiogenetic agents. In conclusion, this review shows that BTCs management is experiencing important innovations, especially in biomarker-based patient selection and in the new emerging therapeutic approach. Many ongoing trials could answer questions regarding the role of molecular inhibitors leading to new therapeutic frontiers for molecular subcategories of BTCs.

Giacomo Aimar ... Massimo Di Maio

Published: October 31, 2021 Explor Target Antitumor Ther. 2021;2:448–464
DOI: https://doi.org/10.37349/etat.2021.00056
This article belongs to the special issue Precision Medicine for Cholangiocarcinoma

Full Text

PDF

Download:82

Times Cited: 4

Patients with unresectable biliary tract carcinomas (BTCs) have a poor prognosis with a median overall survival of fewer than 12 months following systemic chemotherapy. In recent years, the identification of distinct molecular alterations with corresponding targeted therapies is modifying this therapeutic algorithm. The aim of this review is to present an overview of targeted therapy for BTCs, describing published available data and potential future challenges in ongoing trials. From clinicaltrials.gov online database all ongoing trials for BTCs (any stage) was examinated in July 2021, and data regarding study design, disease characteristics and type of treatments were registered. Oncogenic-driven therapy (targeted therapy) was investigated in 67 trials. According to research, 15 ongoing trials (22.4%) are investigating fibroblast growth factor (FGF) receptor (FGFR)-inhibitors in BTCs. Three (18.7%) are open-label randomized multicenter phase 3 trials, 8 (50%) are single-arm phase two trials, and 4 (25%) are phase one studies. Twelve (17.9%) clinical trials dealt with isocitrate dehydrogenase (IDH) 1/2 targeting therapy either in combination with cisplatin (Cis) and gemcitabine (Gem) as first-line treatment for BTCs or in monotherapy in patients with IDH1 mutant advanced malignancies, including cholangiocarcinoma (CCA). Nine (13.4%) clinical trials tested human epidermal growth factor receptor (HER) 2 targeting therapy. Four (44.4%) studies are phase I trials, two (22.2%) are phase I/II trials, and three (33.3%) phase II trials. Rare molecular alterations in BTCs, such as anaplastic lymphoma kinase (ALK), c-ros oncogene1 receptor tyrosine kinase (ROS1), and v-RAF murine sarcoma viral oncogene homologue B1 (BRAF), are also under investigation in a few trials. Forty-four clinical trials (17.2%) are investigating not oncogenic-driven multitarget therapy like multireceptor tyrosin kinase inhibitors and antiangiogenetic agents. In conclusion, this review shows that BTCs management is experiencing important innovations, especially in biomarker-based patient selection and in the new emerging therapeutic approach. Many ongoing trials could answer questions regarding the role of molecular inhibitors leading to new therapeutic frontiers for molecular subcategories of BTCs.

Open Access

Review

Targeted therapy of multiple myeloma

Multiple myeloma (MM) is a malignant proliferative disease of monoclonal plasma cells (PCs) and is characterized by uncontrolled proliferation of PCs and excessive production of specific types of im [...] Read more.

Shan Zhou, Renxi Wang

Published: October 31, 2021 Explor Target Antitumor Ther. 2021;2:465–480
DOI: https://doi.org/10.37349/etat.2021.00057

Full Text

PDF

Download:54

Times Cited: 0

Open Access

Original Article

Performing oncological procedures during COVID-19 outbreak: a picture from an Italian cancer center

Aim: Since SARS-CoV-2 infection rapidly spread around the world, Italy has quickly become one of the most affected countries. Healthcare systems introduced strict infection control measures to ensu [...] Read more.

Aim: Since SARS-CoV-2 infection rapidly spread around the world, Italy has quickly become one of the most affected countries. Healthcare systems introduced strict infection control measures to ensure optimal care, especially in frail groups such as cancer patients (pts). This study investigated the efficacy of SARS-CoV-2 pre-procedure screening and whether COVID-19 influenced timely diagnosis and therapy. Methods: Data of oncological procedures of pts with confirmed or suspected cancer diagnosis, treated at Oncology Department or coming from Emergency Department of San Luigi Gonzaga Hospital between June 2020 and March 2021 were retrospectively collected. A nasopharyngeal swab (NPS) was performed in outpatients 24/48 h before procedures. Inpatients were tested by NPS before and after hospitalization. Results: Two hundred and twenty-one pts were included in this analysis. Median age was 73 years, males were 58%. Eastern Cooperative Oncology Group (ECOG) Performance Status was 0 or 1 in 88% of pts. The most frequent cancer type was lung cancer (57%). Stages IV were 77%. Two hundred and forty-three scheduled procedures were performed with diagnostic (n: 142; 58%), therapeutic (n: 55; 23%), and palliative (n: 46; 19%) intent. One hundred and four and 139 procedures were performed in out- and in-pts, respectively. Of the 234 NPS performed, 10 (4%) were positive. Two pts were infected during hospitalization, 8 in community. Most of them were asymptomatic, while only 2 had mild symptoms. Eight procedures (3%) were postponed, 1 cancelled, while 2 were performed in positive pts. Median time to resolution of the infection was 17 days (11–36). Median delay in the procedures was 25 days (14–55). Five pts started systemic treatment, after a median time of 37.5 days (13–57). Conclusions: SARS-CoV-2 infection led to the postponement of a small, but not negligible percentage of oncological procedures. However, the low infection rate observed suggests that structured screening for COVID-19 is critical for the best management of scheduled procedures during pandemic.

Maristella Bungaro ... Silvia Novello

Published: October 31, 2021 Explor Target Antitumor Ther. 2021;2:481–489
DOI: https://doi.org/10.37349/etat.2021.00058
This article belongs to the special issue COVID-19 and Cancer

Full Text

PDF

Download:34

Times Cited: 0

Aim: Since SARS-CoV-2 infection rapidly spread around the world, Italy has quickly become one of the most affected countries. Healthcare systems introduced strict infection control measures to ensure optimal care, especially in frail groups such as cancer patients (pts). This study investigated the efficacy of SARS-CoV-2 pre-procedure screening and whether COVID-19 influenced timely diagnosis and therapy. Methods: Data of oncological procedures of pts with confirmed or suspected cancer diagnosis, treated at Oncology Department or coming from Emergency Department of San Luigi Gonzaga Hospital between June 2020 and March 2021 were retrospectively collected. A nasopharyngeal swab (NPS) was performed in outpatients 24/48 h before procedures. Inpatients were tested by NPS before and after hospitalization. Results: Two hundred and twenty-one pts were included in this analysis. Median age was 73 years, males were 58%. Eastern Cooperative Oncology Group (ECOG) Performance Status was 0 or 1 in 88% of pts. The most frequent cancer type was lung cancer (57%). Stages IV were 77%. Two hundred and forty-three scheduled procedures were performed with diagnostic (n: 142; 58%), therapeutic (n: 55; 23%), and palliative (n: 46; 19%) intent. One hundred and four and 139 procedures were performed in out- and in-pts, respectively. Of the 234 NPS performed, 10 (4%) were positive. Two pts were infected during hospitalization, 8 in community. Most of them were asymptomatic, while only 2 had mild symptoms. Eight procedures (3%) were postponed, 1 cancelled, while 2 were performed in positive pts. Median time to resolution of the infection was 17 days (11–36). Median delay in the procedures was 25 days (14–55). Five pts started systemic treatment, after a median time of 37.5 days (13–57). Conclusions: SARS-CoV-2 infection led to the postponement of a small, but not negligible percentage of oncological procedures. However, the low infection rate observed suggests that structured screening for COVID-19 is critical for the best management of scheduled procedures during pandemic.

Open Access

Review

Clinical aspect, pathogenesis and therapy options of alopecia induced by hormonal therapy for breast cancer

Adjuvant hormonal therapy is one of the most important treatments of hormone-receptor-positive breast cancer and includes selective estrogen receptor modulators, aromatase inhibitors, and luteinizin [...] Read more.

Alfredo Rossi ... Marta Carlesimo

Published: October 31, 2021 Explor Target Antitumor Ther. 2021;2:490–495
DOI: https://doi.org/10.37349/etat.2021.00059
This article belongs to the special issue Endocrine Resistant Breast Cancer

Full Text

PDF

Download:35

Times Cited: 3

Open Access

Review

Proteolysis-targeting chimeras and their implications in breast cancer

Breast cancer (BC) is a highly heterogeneous neoplasm of the mammary tissue, causing the deaths of a large number of women worldwide. Nearly 70% and 20% of BC cases are estro [...] Read more.

Angeles C. Tecalco-Cruz ... Alberto Rojas-Ochoa

Published: December 31, 2021 Explor Target Antitumor Ther. 2021;2:496–510
DOI: https://doi.org/10.37349/etat.2021.00060
This article belongs to the special issue Proteolysis Targeting Chimera (PROTAC)

Full Text

PDF

Download:100

Times Cited: 4

Open Access

Review

The clinical advances of proteolysis targeting chimeras in oncology

Proteolysis targeting chimeras (PROTACs) are a class of small molecules designed to target proteins for degradation. Their novel and unique modes of action provide PROTACs with the potential for the [...] Read more.

Hao Xie ... Jason B. Fleming

Published: December 31, 2021 Explor Target Antitumor Ther. 2021;2:511–521
DOI: https://doi.org/10.37349/etat.2021.00061
This article belongs to the special issue Proteolysis Targeting Chimera (PROTAC)

Full Text

PDF

Download:228

Times Cited: 21

Open Access

Review

Immunotherapy in head and neck squamous cell carcinoma and rare head and neck malignancies

The dismal prognosis of recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) prompted recent advances in the field of therapeutic approaches beyond cytotoxic cancer therapy. In r [...] Read more.

Stefano Cavalieri ... Laura D. Locati

Published: December 31, 2021 Explor Target Antitumor Ther. 2021;2:522–542
DOI: https://doi.org/10.37349/etat.2021.00062
This article belongs to the special issue Immunotherapy in Cancer Patients

Full Text

PDF

Download:99

Times Cited: 7

Open Access

Original Article

Alterations in the Ca²⁺ toolkit in oesophageal adenocarcinoma

Aim: To investigate alterations in transcription of genes, encoding Ca2+ toolkit proteins, in oesophageal adenocarcinoma (OAC) and to assess associations between gene expression, tumor [...] Read more.

Aim: To investigate alterations in transcription of genes, encoding Ca2+ toolkit proteins, in oesophageal adenocarcinoma (OAC) and to assess associations between gene expression, tumor grade, nodal-metastatic stage, and patient survival. Methods: The expression of 275 transcripts, encoding components of the Ca2+ toolkit, was analyzed in two OAC datasets: the Cancer Genome Atlas [via the University of Alabama Cancer (UALCAN) portal] and the oesophageal-cancer, clinical, and molecular stratification [Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS)] dataset. Effects of differential expression of these genes on patient survival were determined using Kaplan-Meier log-rank tests. OAC grade- and metastatic-stage status was investigated for a subset of genes. Adjustment for the multiplicity of testing was made throughout. Results: Of the 275 Ca2+-toolkit genes analyzed, 75 displayed consistent changes in expression between OAC and normal tissue in both datasets. The channel-encoding genes, N-methyl-D-aspartate receptor 2D (GRIN2D), transient receptor potential (TRP) ion channel classical or canonical 4 (TRPC4), and TRP ion channel melastatin 2 (TRPM2) demonstrated the greatest increase in expression in OAC in both datasets. Nine genes were consistently upregulated in both datasets and were also associated with improved survival outcomes. The 6 top-ranking genes for the weighted significance of altered expression and survival outcomes were selected for further analysis: voltage-gated Ca2+ channel subunit α 1D (CACNA1D), voltage-gated Ca2+ channel auxiliary subunit α2 δ4 (CACNA2D4), junctophilin 1 (JPH1), acid-sensing ion channel 4 (ACCN4), TRPM5, and secretory pathway Ca2+ ATPase 2 (ATP2C2). CACNA1D, JPH1, and ATP2C2 were also upregulated in advanced OAC tumor grades and nodal-metastatic stages in both datasets. Conclusions: This study has unveiled alterations of the Ca2+ toolkit in OAC, compared to normal tissue. Such Ca2+ signalling findings are consistent with those from studies on other cancers. Genes that were consistently upregulated in both datasets might represent useful markers for patient diagnosis. Genes that were consistently upregulated, and which were associated with improved survival, might be useful markers for patient outcome. These survival-associated genes may also represent targets for the development of novel chemotherapeutic agents.

Alana L. Cutliffe ... John J. Mackrill

Published: December 31, 2021 Explor Target Antitumor Ther. 2021;2:543–575
DOI: https://doi.org/10.37349/etat.2021.00063
This article belongs to the special issue Calcium Signaling Apparatus in Cancers

Full Text

PDF

Download:57

Times Cited: 2

Aim: To investigate alterations in transcription of genes, encoding Ca2+ toolkit proteins, in oesophageal adenocarcinoma (OAC) and to assess associations between gene expression, tumor grade, nodal-metastatic stage, and patient survival. Methods: The expression of 275 transcripts, encoding components of the Ca2+ toolkit, was analyzed in two OAC datasets: the Cancer Genome Atlas [via the University of Alabama Cancer (UALCAN) portal] and the oesophageal-cancer, clinical, and molecular stratification [Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS)] dataset. Effects of differential expression of these genes on patient survival were determined using Kaplan-Meier log-rank tests. OAC grade- and metastatic-stage status was investigated for a subset of genes. Adjustment for the multiplicity of testing was made throughout. Results: Of the 275 Ca2+-toolkit genes analyzed, 75 displayed consistent changes in expression between OAC and normal tissue in both datasets. The channel-encoding genes, N-methyl-D-aspartate receptor 2D (GRIN2D), transient receptor potential (TRP) ion channel classical or canonical 4 (TRPC4), and TRP ion channel melastatin 2 (TRPM2) demonstrated the greatest increase in expression in OAC in both datasets. Nine genes were consistently upregulated in both datasets and were also associated with improved survival outcomes. The 6 top-ranking genes for the weighted significance of altered expression and survival outcomes were selected for further analysis: voltage-gated Ca2+ channel subunit α 1D (CACNA1D), voltage-gated Ca2+ channel auxiliary subunit α2 δ4 (CACNA2D4), junctophilin 1 (JPH1), acid-sensing ion channel 4 (ACCN4), TRPM5, and secretory pathway Ca2+ ATPase 2 (ATP2C2). CACNA1D, JPH1, and ATP2C2 were also upregulated in advanced OAC tumor grades and nodal-metastatic stages in both datasets. Conclusions: This study has unveiled alterations of the Ca2+ toolkit in OAC, compared to normal tissue. Such Ca2+ signalling findings are consistent with those from studies on other cancers. Genes that were consistently upregulated in both datasets might represent useful markers for patient diagnosis. Genes that were consistently upregulated, and which were associated with improved survival, might be useful markers for patient outcome. These survival-associated genes may also represent targets for the development of novel chemotherapeutic agents.

Open Access

Original Article

Physical characteristics comparison between maytansinoid-based and auristatin-based antibody-drug conjugates

Aim: Direct analytical comparison of two major drug-linkers in the antibody-drug conjugate (ADC) field was conducted. Methods: Four different analytical methods [AlogP calculation, reverse phase (RP) high-performance liquid chrom [...] Read more.

Tomohiro Fujii ... Yutaka Matsuda

Published: December 31, 2021 Explor Target Antitumor Ther. 2021;2:576–585
DOI: https://doi.org/10.37349/etat.2021.00064
This article belongs to the special issue Antibody-Drug Conjugates

Full Text

PDF

Download:181

Times Cited: 12

Open Access

Review

Interface between obesity with dysfunctional metabolism and inflammation, and the triple-negative breast cancer in African American women

Obesity has dramatically increased over the past fifty years. In the last decade, it has been noted that augmented body mass, metabolic abnormalities, and the relevant “obese” [...] Read more.

Katarzyna Rygiel

Published: December 31, 2021 Explor Target Antitumor Ther. 2021;2:602–616
DOI: https://doi.org/10.37349/etat.2021.00066
This article belongs to the special issue Endocrine Resistant Breast Cancer

Full Text

PDF

Download:56

Times Cited: 1

Open Access

Original Article

The bromodomain and extra-terminal domain degrader MZ1 exhibits preclinical anti-tumoral activity in diffuse large B-cell lymphoma of the activated B cell-like type

Aim: Bromodomain and extra-terminal domain (BET) proteins are epigenetic readers that play a fundamental role in transcription regulation. Preclinical and early clinical evidence sustain BET targ [...] Read more.

Aim: Bromodomain and extra-terminal domain (BET) proteins are epigenetic readers that play a fundamental role in transcription regulation. Preclinical and early clinical evidence sustain BET targeting as an anti-cancer approach. BET degraders are chimeric compounds comprising of a BET inhibitor, which allows the binding to BET bromodomains, linked to a small molecule, binder for an E3 ubiquitin ligase complex, triggering BET proteins degradation via the proteasome. These degraders, called proteolysis-targeting chimeras (PROTACs), can exhibit greater target specificity compared to BET inhibitors and overcome some of their limitations, such as the upregulation of the BET proteins themselves. Here are presented data on the anti-tumor activity and the mechanism of action of the BET degrader MZ1 in diffuse large B cell lymphoma (DLBCL) of the activated B-cell like (ABC, ABC DLBCL), using a BET inhibitor as a comparison. Methods: Established lymphoma cell lines were exposed for 72 h to increasing doses of the compounds. Cell proliferation was evaluated by using an 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazoliumbromide (MTT) assay. Fluorescent-Activated Cell Sorter (FACS) analysis was performed to measure apoptotic activation and RNA sequencing (RNA-Seq) to study the transcriptional changes induced by the compounds. Results: MZ1, and not its negative control epimer cisMZ1, was very active with a median half maximal inhibitory concentration (IC50) of 49 nmol/L. MZ1 was more in vitro active than the BET inhibitor birabresib (OTX015). Importantly, MZ1 induced cell death in all the ABC DLBCL cell lines, while the BET inhibitor was cytotoxic only in a fraction of them. BET degrader and inhibitor shared partially similar changes at transcriptome level but the MZ1 effect was stronger and overlapped with that caused cyclin-dependent kinase 9 (CDK9) inhibition. Conclusions: The BET degrader MZ1 had strong cytotoxic activity in all the ABC DLBCL cell lines that were tested, and, at least in vitro, it elicited more profound effects than BET inhibitors, and encourages further investigations.

Chiara Tarantelli ... Francesco Bertoni

Published: December 31, 2021 Explor Target Antitumor Ther. 2021;2:586–601
DOI: https://doi.org/10.37349/etat.2021.00065
This article belongs to the special issue Proteolysis Targeting Chimera (PROTAC)

Full Text

PDF

Download:105

Times Cited: 5

Aim: Bromodomain and extra-terminal domain (BET) proteins are epigenetic readers that play a fundamental role in transcription regulation. Preclinical and early clinical evidence sustain BET targeting as an anti-cancer approach. BET degraders are chimeric compounds comprising of a BET inhibitor, which allows the binding to BET bromodomains, linked to a small molecule, binder for an E3 ubiquitin ligase complex, triggering BET proteins degradation via the proteasome. These degraders, called proteolysis-targeting chimeras (PROTACs), can exhibit greater target specificity compared to BET inhibitors and overcome some of their limitations, such as the upregulation of the BET proteins themselves. Here are presented data on the anti-tumor activity and the mechanism of action of the BET degrader MZ1 in diffuse large B cell lymphoma (DLBCL) of the activated B-cell like (ABC, ABC DLBCL), using a BET inhibitor as a comparison. Methods: Established lymphoma cell lines were exposed for 72 h to increasing doses of the compounds. Cell proliferation was evaluated by using an 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazoliumbromide (MTT) assay. Fluorescent-Activated Cell Sorter (FACS) analysis was performed to measure apoptotic activation and RNA sequencing (RNA-Seq) to study the transcriptional changes induced by the compounds. Results: MZ1, and not its negative control epimer cisMZ1, was very active with a median half maximal inhibitory concentration (IC50) of 49 nmol/L. MZ1 was more in vitro active than the BET inhibitor birabresib (OTX015). Importantly, MZ1 induced cell death in all the ABC DLBCL cell lines, while the BET inhibitor was cytotoxic only in a fraction of them. BET degrader and inhibitor shared partially similar changes at transcriptome level but the MZ1 effect was stronger and overlapped with that caused cyclin-dependent kinase 9 (CDK9) inhibition. Conclusions: The BET degrader MZ1 had strong cytotoxic activity in all the ABC DLBCL cell lines that were tested, and, at least in vitro, it elicited more profound effects than BET inhibitors, and encourages further investigations.

Open Access

Review

Antibody-drug conjugate therapies in multiple myeloma—what’s next on the horizon?

Targeted immunotherapy has arisen over the past decade to the forefront of cancer care. Notably, targeted therapies such as antibody-drug conjugates (ADCs) are becoming more recognized for a novel a [...] Read more.

Monique Hartley-Brown, Paul Richardson

Published: January 14, 2022 Explor Target Antitumor Ther. 2022;3:1–10
DOI: https://doi.org/10.37349/etat.2022.00067
This article belongs to the special issue Antibody-Drug Conjugates

Full Text

PDF

Download:126

Times Cited: 5