Oncotarget

BUFFALO, NY- April 10, 2024 – A new #researchpaper was #published in Oncotarget's Volume 15 on April 8, 2024, entitled, “Exploring the role of GHRH antagonist MIA-602 in overcoming Doxorubicin-resistance in acute myeloid leukemia.”

Acute myeloid leukemia (AML) is characterized by the rapid proliferation of mutagenic hematopoietic progenitors in the bone marrow. Conventional therapies include chemotherapy and bone marrow stem cell transplantation; however, they are often associated with poor prognosis. Notably, growth hormone-releasing hormone (GHRH) receptor antagonist MIA-602 has been shown to impede the growth of various human cancer cell lines, including AML. In this new study, researchers Simonetta I. Gaumond, Rama Abdin, Joel Costoya, Andrew V. Schally, and Joaquin J. Jimenez from the University of Miami, Florida Atlantic University and Veterans Affairs Medical Center, Miami examined the impact of MIA-602 as monotherapy and in combination with Doxorubicin on three Doxorubicin-resistant AML cell lines, KG-1A, U-937, and K-562.

“Given the role of GHRH in multiple cancer types, it is possible that GHRH antagonists may offer an alternative treatment approach for AML as well as drug-resistant AML, which may circumvent the side effects associated with standard chemotherapy.”

The in vitro results revealed a significant reduction in cell viability for all treated wild-type cells. Doxorubicin-resistant clones were similarly susceptible to MIA-602 as the wild-type counterpart. Their in vivo experiment of xenografted nude mice with Doxorubicin-resistant K-562 revealed a reduction in tumor volume with MIA-602 treatment compared to control.

“Our study demonstrates that these three AML cell lines, and their Doxorubicin-resistant clones, are susceptible to GHRH antagonist MIA-602.”

DOI - https://doi.org/10.18632/oncotarget.28579

Correspondence to - Simonetta I. Gaumond - [email protected]

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Keywords - cancer, leukemia, AML, resistance, growth hormone-releasing hormone, MIA-602

About Oncotarget

Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.

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

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Cancer therapy has come a long way from its one-size-fits-all beginning to the awakening era of personalized medicine. This change has been largely driven by the discovery of biomarkers. Biomarkers can help refine patient selection for specific therapies. A blend of causal and correlative approaches is needed to elucidate the full potential of biomarkers in cancer research. This fusion of methodologies allows for a comprehensive exploration of biomarker efficacy, leading to more accurate predictions of drug response.

In a new paper, researchers Alberto Moscona-Nissan, Karl J. Habashy, Victor A. Arrieta, Adam M. Sonabend, and Crismita Dmello from the Universidad Panamericana School of Medicine, Northwestern University and Universidad Nacional Autónoma de México discuss causal and correlative approaches to identify potential biomarkers for predicting response to paclitaxel — a commonly used chemotherapeutic agent. On February 8, 2024, their research perspective was published in Oncotarget’s Volume 15, entitled, “Combining causal and correlative approaches to discover biomarkers of response to paclitaxel.”

“[…] studying the combination of non-overlapping biomarkers’ expression, in addition to clinical and sociodemographic data could generate predictive models for paclitaxel susceptibility.”

Full blog - https://www.oncotarget.org/2024/03/28/identifying-biomarkers-for-predicting-paclitaxel-response/

Paper DOI - https://doi.org/10.18632/oncotarget.28549

Correspondence to - Crismita Dmello - [email protected], and Adam M. Sonabend - [email protected]

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Keywords - cancer, glioblastoma, predictive biomarker, CRISPR screen, paclitaxel

About Oncotarget

Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.

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BUFFALO, NY- March 27, 2024 – A new #research paper was #published in Oncotarget's Volume 15 on March 19, 2024, entitled, “Durvalumab and tremelimumab before surgery in patients with hormone receptor positive, HER2-negative stage II–III breast cancer.”

In this new study, researchers Haven R. Garber, Sreyashi Basu, Sonali Jindal, Zhong He, Khoi Chu, Akshara Singareeka Raghavendra, Clinton Yam, Lumarie Santiago, Beatriz E. Adrada, Padmanee Sharma, Elizabeth A. Mittendorf, and Jennifer K. Litton from the University of Texas MD Anderson Cancer Center, Brigham and Women’s Hospital, Dana-Farber Brigham Cancer Center, and Harvard Medical School conducted a clinical trial to assess the feasibility of enrolling patients with Stage II or III hormone receptor positive (HR+)/HER2-negative breast cancer to pre-operative dual PD-L1/CTLA-4 checkpoint inhibition administered prior to neoadjuvant chemotherapy (NACT).

“This feasibility study was conducted to begin testing the hypothesis that dual checkpoint blockade would increase TIL and enhance the response to subsequent NACT in patients with stage II or III HR+/HER2-negative breast cancer.”

Eight eligible patients were treated with upfront durvalumab and tremelimumab for two cycles. Patients then received NACT prior to breast surgery. Seven patients had baseline and interval breast ultrasounds after combination immunotherapy and the responses were mixed: 3/7 patients experienced a ≥30% decrease in tumor volume, 3/7 a ≥30% increase, and 1 patient had stable disease. At the time of breast surgery, 1/8 patients had a pathologic complete response (pCR).

The trial was stopped early after 3 of 8 patients experienced immunotherapy-related toxicity or suspected disease progression that prompted discontinuation or a delay in the administration of NACT. Two patients experienced grade 3 immune-related adverse events (1 with colitis, 1 with endocrinopathy). Analysis of the tumor microenvironment after combination immunotherapy did not show a significant change in immune cell subsets from baseline.

“There was limited benefit for dual checkpoint blockade administered prior to NACT in our study of 8 patients with HR+/HER2-negative breast cancer.”

DOI - https://doi.org/10.18632/oncotarget.28567

Correspondence to - Haven R. Garber - [email protected]

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Keywords - cancer, breast cancer, ER positive, immunotherapy, neoadjuvant chemotherapy, tumor microenvironment

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Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.

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

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BUFFALO, NY- March 25, 2024 – A new #research paper was #published in Oncotarget's Volume 15 on March 14, 2024, entitled, “ABT199/venetoclax synergism with thiotepa enhances the cytotoxicity of fludarabine, cladribine and busulfan in AML cells.”

ABT199/venetoclax, an inhibitor of the pro-survival BCL-2 protein, has improved AML treatment. Its efficacy in hematopoietic stem cell transplantation (HSCT), when combined with other chemotherapeutic drugs, has not been thoroughly investigated. In this new study, researchers Benigno C. Valdez, Bin Yuan, David Murray, Jeremy L. Ramdial, Uday Popat, Yago Nieto, and Borje S. Andersson from The University of Texas MD Anderson Cancer Center and the University of Alberta demonstrate the synergistic cytotoxicity of ABT199/venetoclax with the DNA alkylator thiotepa (Thio) in AML cells.

“The results may provide relevant information for the design of clinical trials using these drugs to circumvent recognized drug-resistance mechanisms when used as part of pre-transplant conditioning regimens for AML patients undergoing allogenic HSCT.”

Cleavage of Caspase 3, PARP1 and HSP90, as well as increased Annexin V positivity, suggest potent activation of apoptosis by this two-drug combination; increased levels of γ-H2AX, P-CHK1 (S317), P-CHK2 (S19) and P-SMC1 (S957) indicate an enhanced DNA damage response. Likewise, the increased level of P-SAPK/JNK (T183/Y185) and decreased P-PI3Kp85 (Y458) suggest enhanced activation of stress signaling pathways. These molecular readouts were synergistically enhanced when ABT199/venetoclax and Thio were combined with fludarabine, cladribine and busulfan.

The five-drug combination decreased the levels of BCL-2, BCL-xL and MCL-1, suggesting its potential clinical relevance in overcoming ABT199/venetoclax resistance. Moreover, this combination is active against P53-negative and FLT3-ITD-positive cell lines. Enhanced activation of apoptosis was observed in leukemia patient-derived cell samples exposed to the five-drug combination, suggesting a clinical relevance.

“The results provide a rationale for clinical trials using these two- and five-drug combinations as part of a conditioning regimen for AML patients undergoing HSCT.”

DOI - https://doi.org/10.18632/oncotarget.28563

Correspondence to - Benigno C. Valdez - [email protected]

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Keywords - cancer, acute myeloid leukemia, aml, pre-transplant regimens, venetoclax, thiotepa, busulfan

About Oncotarget

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BUFFALO, NY- March 20, 2024 – A new #research paper was #published in Oncotarget's Volume 15 on March 14, 2024, entitled, “Analytical validation of NeXT Personal®, an ultra-sensitive personalized circulating tumor DNA assay.”

In this new study, researchers Josette Northcott, Gabor Bartha, Jason Harris, Conan Li, Fabio C.P. Navarro, Rachel Marty Pyke, Manqing Hong, Qi Zhang, Shuyuan Ma, Tina X. Chen, Janet Lai, Nitin Udar, Juan-Sebastian Saldivar, Erin Ayash, Joshua Anderson, Jiang Li, Tiange Cui, Tu Le, Ruthie Chow, Randy Jerel Velasco, Chris Mallo, Rose Santiago, Robert C. Bruce, Laurie J. Goodman, Yi Chen, Dan Norton, Richard O. Chen, and John M. Lyle from Personalis, Inc. describe the analytical validation of NeXT Personal®, an ultra-sensitive, tumor-informed circulating tumor DNA (ctDNA) assay for detecting residual disease, monitoring therapy response, and detecting recurrence in patients diagnosed with solid tumor cancers.

“NeXT Personal uses whole genome sequencing of tumor and matched normal samples combined with advanced analytics to accurately identify up to ~1,800 somatic variants specific to the patient’s tumor.”

A personalized panel is created, targeting these variants and then used to sequence cell-free DNA extracted from patient plasma samples for ultra-sensitive detection of ctDNA. The NeXT Personal analytical validation is based on panels designed from tumor and matched normal samples from two cell lines, and from 123 patients across nine cancer types. Analytical measurements demonstrated a detection threshold of 1.67 parts per million (PPM) with a limit of detection at 95% (LOD95) of 3.45 PPM. NeXT Personal showed linearity over a range of 0.8 to 300,000 PPM (Pearson correlation coefficient = 0.9998). Precision varied from a coefficient of variation of 12.8% to 3.6% over a range of 25 to 25,000 PPM. The assay targets 99.9% specificity, with this validation study measuring 100% specificity and in silico methods giving a confidence interval of 99.92 to 100%.

“In summary, this study demonstrates NeXT Personal as an ultra-sensitive, highly quantitative and robust ctDNA assay that can be used to detect residual disease, monitor treatment response, and detect recurrence in patients.”

DOI - https://doi.org/10.18632/oncotarget.28565

Correspondence to - John M. Lyle - [email protected]

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Keywords - cancer, circulating tumor DNA, whole genome sequencing, molecular residual disease, tumor-informed assay, analytical validation

Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.

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BUFFALO, NY- March 19, 2024 – A new #research perspective was #published by Mikhail V. Blagosklonny M.D., Ph.D., from Roswell Park Comprehensive Cancer Center in Oncotarget's Volume 15 on March 15, 2024, entitled, “From osimertinib to preemptive combinations.”

“Here, I suggest that while first-line osimertinib extends median progression-free survival (PFS) in EGFR-mutant lung cancer compared to first-generation TKIs, it reduces individual PFS in 15–20% of patients compared to first-generation TKIs. Since detecting a single resistant cell before treatment is usually impossible, osimertinib must be used in all patients as a first-line treatment, raising median PFS overall but harming some.

The simplest remedy is a preemptive combination (PC) of osimertinib and gefitinib. A comprehensive PC (osimertinib, afatinib/gefitinib, and capmatinib) could dramatically increase PFS for 80% of patients compared to osimertinib alone, without harming anyone. This article also explores PCs for MET-driven lung cancer.”

DOI - https://doi.org/10.18632/oncotarget.28569

Correspondence to - Mikhail V. Blagosklonny - [email protected], [email protected]

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Keywords - cancer, lung cancer, NSCLC, EGFR, resistance, afatinib, gefitinib, capmatinib

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Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.

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BUFFALO, NY- March 18, 2024 – A new #researchpaper was #published in Oncotarget's Volume 15 on March 14, 2024, entitled, “G-quadruplex landscape and its regulation revealed by a new antibody capture method.”

In this new study, researchers Subhamoy Datta, Manthan Patel, Chakkarai Sathyaseelan, Chandrama Ghosh, Akanksha Mudgal, Divyesh Patel, Thenmalarchelvi Rathinavelan, and Umashankar Singh from the Indian Institute of Technology Gandhinagar, Indian Institute of Technology Hyderabad, Queen Mary University of London, Bar-Ilan University, Medical University of Lublin, and the University of Helsinki discuss a secondary structure of DNA that has attracted wide interest, G-quadruplexes or G4s.

“Our understanding of DNA G-quadruplexes (G4s) from in vitro studies has been complemented by genome-wide G4 landscapes from cultured cells.”

Conventionally, the formation of G4s is accepted to depend on G-repeats such that they form tetrads. However, genome-wide G4s characterized through high-throughput sequencing suggest that these structures form at a large number of regions with no such canonical G4-forming signatures. Many G4-binding proteins have been described with no evidence for any protein that binds to and stabilizes G4s.

“It remains unknown what fraction of G4s formed in human cells are protein-bound.”

The G4-chromatin immunoprecipitation (G4-ChIP) method hitherto employed to describe G4 landscapes preferentially reports G4s that get crosslinked to proteins in their proximity. The current understanding of the G4 landscape is biased against representation of G4s which escape crosslinking as they are not stabilized by protein-binding and presumably transient. The researchers reported a protocol that captures G4s from the cells efficiently without any bias as well as eliminates the detection of G4s formed artifactually on crosslinked sheared chromatin post-fixation. They discovered that G4s form sparingly at SINEs (short interspersed nuclear elements). An application of this method shows that depletion of a repeat-binding protein CGGBP1 enhances net G4 capture at CGGBP1-dependent CTCF-binding sites and regions of sharp interstrand G/C-skew transitions.

“The AbC G4-ChIP presents a powerful technique to decipher the cellular G4 landscape and its regulation and it has the potential to be adapted for discovering any DNA secondary structures genome-wide against which reliable antibodies are available.”

DOI - https://doi.org/10.18632/oncotarget.28564

Correspondence to - Umashankar Singh - [email protected]

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Keywords - cancer, DNA G-quadruplexes, G4-ChIP, CGGBP1, CTCF, G/C-skew

Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.

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The relentless search for effective cancer therapies has led to numerous breakthroughs in drug discovery and development. Advancements have emerged in recent years through the promising avenue of combination therapy, where two or more drugs are used synergistically to enhance their collective therapeutic effect. This strategy has shown significant potential in overcoming drug resistance, reducing side effects, and improving patient survival rates.

In a new study, researchers Thomas M. Cardillo, Maria B. Zalath, Roberto Arrojo, Robert M. Sharkey, Serengulam V. Govindan, Chien-Hsing Chang, and David M. Goldenberg from Gilead Sciences and the Center for Molecular Medicine and Immunology demonstrated the significant antitumor effects of Sacituzumab govitecan, an anti-Trop-2-SN-38 antibody-drug conjugate, in combination with platinum-based chemotherapy. On February 22, 2024, their research paper was published in Oncotarget, entitled, “Sacituzumab govitecan plus platinum-based chemotherapy mediates significant antitumor effects in triple-negative breast, urinary bladder, and small-cell lung carcinomas.”

Full blog - https://www.oncotarget.org/2024/03/14/antitumor-effects-of-sacituzumab-govitecan-plus-platinum-based-chemotherapy/

Paper DOI - https://doi.org/10.18632/oncotarget.28559

Correspondence to - Thomas M. Cardillo - [email protected]

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Keywords - cancer, sacituzumab govitecan, Trop-2, SN-38, carboplatin, cisplatin

About Oncotarget

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.

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BUFFALO, NY- March 11, 2024 – Impact Journals publishes #scholarly journals in the #biomedical sciences with a focus on all areas of cancer and aging research. Oncotarget is one of the most prominent journals published by Impact Journals.

Impact Journals will be participating as an exhibitor at the American Association for Cancer Research (AACR) Annual Meeting 2024 from April 5-10 at the San Diego Convention Center in San Diego, California. This year, the AACR meeting theme is “Inspiring Science • Fueling Progress • Revolutionizing Care.”

Visit booth number 4159 at the AACR Annual Meeting 2024 to connect with members of the Oncotarget team.

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Oncotarget (a primarily oncology-focused, peer-reviewed, open-access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.

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BUFFALO, NY- March 6, 2024 – A new #researchpaper was #published in Oncotarget's Volume 15 on March 5, 2024, entitled, “GZ17-6.02 interacts with proteasome inhibitors to kill multiple myeloma cells.”

In this new study, researchers Laurence Booth, Jane L. Roberts, Cameron West, and Paul Dent from Virginia Commonwealth University and Genzada Pharmaceuticals investigated GZ17-6.02, a synthetically manufactured compound containing isovanillin, harmine and curcumin, in multiple myeloma cells. GZ17-6.02 has undergone phase I evaluation in patients with solid tumors (NCT03775525) with a recommended phase 2 dose (RP2D) of 375 mg PO BID. GZ17-6.02 was more efficacious as a single agent at killing multiple myeloma cells than had previously been observed in solid tumor cell types.

“GZ17-6.02 interacted with proteasome inhibitors in a greater than additive fashion to kill myeloma cells and alone it killed inhibitor-resistant cells to a similar extent.”

The drug combination of GZ17-6.02 and bortezomib activated ATM, the AMPK and PERK and inactivated ULK1, mTORC1, eIF2α, NFκB and the Hippo pathway. The combination increased ATG13 S318 phosphorylation and the expression of Beclin1, ATG5, BAK and BIM, and reduced the levels of BCL-XL and MCL1. GZ17-6.02 interacted with bortezomib to enhance autophagosome formation and autophagic flux, and knock down of ATM, AMPKα, ULK1, Beclin1 or ATG5 significantly reduced both autophagy and tumor cell killing. Knock down of BAK and BIM significantly reduced tumor cell killing.

The expression of HDACs1/2/3 was significantly reduced beyond that previously observed in solid tumor cells and required autophagy. This was associated with increased acetylation and methylation of histone H3. Combined knock down of HDACs1/2/3 caused activation of ATM and the AMPK and caused inactivation of ULK1, mTORC1, NFκB and the Hippo pathway. HDAC knock down also enhanced ATG13 phosphorylation, increased BAK levels and reduced those of BCL-XL.

“Collectively, our present studies support performing additional in vivo studies with multiple myeloma cells.”

DOI - https://doi.org/10.18632/oncotarget.28558

Correspondence to - Paul Dent - [email protected]

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Keywords - cancer, autophagy, ER stress, GZ17-6.02, bortezomib, proteasome inhibitor

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