Article
Cell Biology
Yunyun Jin, Qianqian Liu, Peng Chen, Siyuan Zhao, Wenhao Jiang, Fanhua Wang, Peng Li, Yuanjin Zhang, Weiqiang Lu, Tao P. Zhong, Xinran Ma, Xin Wang, Alison Gartland, Ning Wang, Karan Mehul Shah, Hankun Zhang, Xu Cao, Lei Yang, Mingyao Liu, Jian Luo
Summary: This study found that EP4 expression is increased in injured articular cartilage in both humans and mice. Deleting EP4 in cartilage promotes tissue regeneration and enhances stable mature articular cartilage formation. A novel EP4 antagonist called HL-43 is shown to enhance cartilage anabolism, suppress catabolism, prevent fibrocartilage formation, and reduce joint pain in animal models. The study suggests that EP4 can be a promising therapeutic target for cartilage regeneration and that HL-43 has the potential for clinical use in cartilage repair and regeneration.
Article
Oncology
Lucjan Wyrwicz, Mark Saunders, Marcia Hall, John Ng, Theodore Hong, Sherry Xu, Justin Lucas, Xuyang Lu, Nathan Lautermilch, Silvia Formenti, Robert Glynne-Jones
Summary: This study aimed to assess the safety and efficacy of AN0025 in combination with preoperative radiotherapy and chemotherapy for locally advanced rectal cancer. The results showed that the treatment with AN0025 was well-tolerated and induced both a pathological and complete clinical response.
RADIOTHERAPY AND ONCOLOGY
(2023)
Article
Cell Biology
Gibran Alejandro Estua-Acosta, Beatriz Buentello-Volante, Fatima Sofia Magana-Guerrero, Jose Eduardo-Aguayo Flores, Oscar Vivanco-Rojas, Ilse Castro-Salas, Karla Zarco-Avila, Mariana A. Garcia-Mejia, Yonathan Garfias
Summary: This research describes the impact of prostaglandin E-2 (PGE(2)) secreted by human amniotic membrane mesenchymal stem cells (hAM-MSCs) on neutrophil extracellular trap (NET) release and identifies the role of its receptors (EP2/EP4) in PAD-4 and NF kappa B activity in neutrophils.
Article
Oncology
Mrinal M. M. Gounder, Todd M. M. Bauer, Gary K. K. Schwartz, Amy M. M. Weise, Patricia LoRusso, Prasanna Kumar, Ben Tao, Ying Hong, Parul Patel, Yasong Lu, Arnaud Lesegretain, Vijaya G. G. Tirunagaru, Feng Xu, Robert C. C. Doebele, David S. S. Hong
Summary: This study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of milademetan, an MDM2 inhibitor, in patients with advanced cancers. The study found that an intermittent dosing schedule of milademetan can mitigate dose-limiting hematologic abnormalities while maintaining efficacy.
JOURNAL OF CLINICAL ONCOLOGY
(2023)
Article
Biotechnology & Applied Microbiology
Fenne L. Komdeur, Amrita Singh, Stephanie van de Wall, Janneke J. M. Meulenberg, Annemarie Boerma, Baukje Nynke Hoogeboom, Sterre T. Paijens, Cesar Oyarce, Marco de Bruyn, Ed Schuuring, Joke Regts, Ruben Marra, Naomi Werner, Jessica Sluis, Ate G. J. van der Zee, Jan C. Wilschut, Derk P. Allersma, Coba J. van Zanten, Jos G. W. Kosterink, Annelies Jorritsma-Smit, Refika Yigit, Hans W. Nijman, Toos Daemen
Summary: The first-in-human phase I trial of Vvax001, a therapeutic cancer vaccine against HPV-induced cancers, showed that it was safe and induced immune responses in all participants. Further clinical evaluation of Vvax001 in patients with HPV-related malignancies is strongly supported by these results.
Article
Oncology
Patrick A. Ott, Matthew Nazzaro, Kathleen L. Pfaff, Evisa Gjini, Kristen D. Felt, Jacquelyn O. Wolff, Elizabeth Buchbinder, Rizwan Haq, Ryan J. Sullivan, Donald P. Lawrence, David F. McDermott, Mariano Severgnini, Anita Giobbie-Hurder, Scott J. Rodig, F. Stephen Hodi
Summary: The combination therapy of Tremelimumab and MEDI3617 was found to be safe in patients with advanced melanoma, but no significant immune-related complete or partial responses were observed. Inhibition of angiopoietin-2 combined with immune checkpoint inhibition deserves further exploration.
JOURNAL FOR IMMUNOTHERAPY OF CANCER
(2021)
Article
Medicine, General & Internal
Jeroen H. A. Creemers, Inka Pawlitzky, Konstantina Grosios, Uzi Gileadi, Mark R. Middleton, Winald R. Gerritsen, Niven Mehra, Licia Rivoltini, Ian Walters, Carl G. Figdor, Petronella B. Ottevanger, I. Jolanda M. de Vries
Summary: This study aims to investigate the safety, tolerability, and immune-modulatory activity of PRECIOUS-01 in patients with advanced NY-ESO-1-expressing solid tumors. The study is a first-in-human, open-label phase I trial with dose escalation to determine the maximum tolerated dose and/or recommended phase II dose.
Article
Oncology
Adi Diab, Omid Hamid, John A. Thompson, Willeke Ros, Ferry A. L. M. Eskens, Toshihiko Doi, Siwen Hu-Lieskovan, Samuel J. Klempner, Bishu Ganguly, Catherine Fleener, Xiao Wang, Tenshang Joh, Ken Liao, Shahram Salek-Ardakani, Carrie Turich Taylor, Jeffrey Chou, Anthony B. El-Khoueiry
Summary: This study investigates the potential of Ivuxolimab in the treatment of cancer. The results demonstrate that Ivuxolimab is well tolerated and safe, and shows anti-tumor activity. Additionally, this study also finds that Ivuxolimab can activate the immune system, enhancing T-cell activation and proliferation, and has a certain control effect on tumors.
CLINICAL CANCER RESEARCH
(2022)
Article
Oncology
Tae Won Kim, Howard A. Burris, Maria J. de Miguel Luken, Michael J. Pishvaian, Yung-Jue Bang, Michael Gordon, Ahmad Awada, D. Ross Camidge, F. Stephen Hodi, Grant A. McArthur, Wilson H. Miller, Andres Cervantes, Laura Q. Chow, Alexander M. Lesokhin, Annemie Rutten, Mario Sznol, Deepali Rishipathak, Shang-Chiung Chen, Eric Stefanich, Tony Pourmohamad, Maria Anderson, Jeong Kim, Mahrukh Huseni, Ina Rhee, Lillian L. Siu
Summary: This study evaluated the first-in-human use of MOXR0916, a humanized monoclonal antibody, in the treatment of advanced solid tumors. The results showed that MOXR0916 was well tolerated and demonstrated evidence of tumor immune activation. Although objective responses were rare with monotherapy, further investigation in combination with PD-1/PD-L1 antagonists is warranted.
CLINICAL CANCER RESEARCH
(2022)
Article
Oncology
Richard D. Baird, Constanza Linossi, Mark Middleton, Simon Lord, Adrian Harris, Jordi Rodon, Christof Zitt, Ulrike Fiedler, Keith M. Dawson, Nicolas Leupin, Michael T. Stumpp, Andreas Harstrick, Analia Azaro, Stefanie Fischer, Aurelius Omlin
Summary: MP0250 is a first-in-class DARPin drug candidate with suitable tolerability and appropriate pharmacokinetic properties for further development in combination with other anticancer therapies. Signs of single-agent antitumor activity were observed.
JOURNAL OF CLINICAL ONCOLOGY
(2021)
Article
Oncology
Khanh T. Do, Laura Quan Man Chow, Karen Reckamp, Rachel E. Sanborn, Howard Burris, Francisco Robert, D. Ross Camidge, Conor E. Steuer, John H. Strickler, Amy Weise, Jennifer M. Specht, Martin Gutierrez, Peter Haughney, Shawna Hengel, Christina Louise Derleth, Timothy A. Yap
Summary: SGN-2FF, a potent small-molecule inhibitor of glycoprotein fucosylation, demonstrated dose-proportional pharmacokinetics, evidence of pharmacodynamic target inhibition of glycoprotein fucosylation, and preliminary antitumor activity in advanced solid tumors. However, it was associated with thromboembolic events that led to study termination.
Article
Oncology
Maria M. Rubinstein, Rachel N. Grisham, Karen Cadoo, Chrisann Kyi, William P. Tew, Claire F. Friedman, Roisin E. O'Cearbhaill, Dmitriy Zamarin, Qin Zhou, Alexia Iasonos, Ines Nikolovski, Hongmei Xu, Krysten N. Soldan, Imogen Caird, Madhuri Martin, Joyce Guillen, Khalil T. Eid, Carol Aghajanian, Vicky Makker
Summary: The study evaluated the safety and tolerability of combination therapy with Selinexor and CP in advanced ovarian and endometrial cancers, showing promising efficacy. The most common treatment-related adverse events included thrombocytopenia, leukopenia, and hyperglycemia.
GYNECOLOGIC ONCOLOGY
(2021)
Article
Oncology
Alessandra Rinah Nogueira Voges, Rodrigo Ubukata, Karina Velloso Braga Yazbek, Otavia Luisa Caballero, Andres Mario Salazar, Cristina de Oliveira Massoco, Maria Lucia Zaidan Dagli
Summary: The study investigated the clinical efficacy, quality of life, and adverse events of poly-ICLC treatment in dogs with advanced cancers. The results showed that the treatment was well tolerated in dogs with some showing clinical benefit and improved quality of life.
Article
Cell Biology
Ignacio Melero, Tamara Tanos, Mariana Bustamante, Miguel F. Sanmamed, Emiliano Calvo, Irene Moreno, Victor Moreno, Tatiana Hernandez, Maria Martinez Garcia, Alejo Rodriguez-Vida, Josep Tabernero, Analia Azaro, Mariano Ponz-Sarvise, Iben Spanggaard, Kristoffer Rohrberg, Ernesto Guarin, Eveline Nuesch, Iakov I. Davydov, Chiahuey Ooi, Jose Duarte, Evelyne Chesne, Christine McIntyre, Maurizio Ceppi, Marta Canamero, Oliver Krieter
Summary: This first-in-human study evaluated the effectiveness of RO7122290, a bispecific fusion protein, in stimulating T cells for improved tumor cell killing in FAP-expressing tumors. The study involved administering escalating doses of RO7122290, both as a single agent and in combination with atezolizumab, to patients with advanced or metastatic solid tumors. The results showed promising pharmacokinetics and treatment-induced changes in peripheral and tissue biomarkers, supporting further evaluation of RO7122290 in combination with immune-oncology agents for solid tumor treatment.
SCIENCE TRANSLATIONAL MEDICINE
(2023)
Article
Oncology
Xiaojiang Duan, Lei Xia, Zhuochen Zhang, Yanan Ren, Martin G. Pomper, Steven P. Rowe, Xuesong Li, Nan Li, Ning Zhang, Hua Zhu, Zhi Yang, Xinan Sheng, Xing Yang
Summary: This study developed a bicyclic peptide-based radiotracer Ga-68-N188 for targeting Nectin-4 and conducted preclinical and translational studies. The results demonstrated that Ga-68-N188 has high affinity and specific uptake for Nectin-4, and can quantitatively image the expression level of Nectin-4 in different organs. The findings of this study provide a companion diagnostic tool for treatments targeting Nectin-4.
CLINICAL CANCER RESEARCH
(2023)
Article
Oncology
Aung Naing, Alain P. Algazi, Gerald S. Falchook, Benjamin C. Creelan, John Powderly, Seth Rosen, Minal Barve, Niharika B. Mettu, Pierre L. Triozzi, John Hamm, Gongfu Zhou, Chris Walker, Zhiwan Dong, Manish R. Patel
Summary: This study evaluated the safety and efficacy of the combination therapy of the IDO1 inhibitor epacadostat and the PD-L1 monoclonal antibody durvalumab in patients with advanced solid tumors. The study findings showed that the combination therapy had common adverse events and low objective response rate, and a higher dose of epacadostat was needed for sufficient drug effect.
Article
Oncology
Justin T. Moyers, Roberto Carmagnani Pestana, Jason Roszik, David S. Hong, Aung Naing, Siqing Fu, Sarina Piha-Paul, Timothy A. Yap, Daniel Karp, Jordi Rodon, Andy Livingston, Maria Alejandra Zarzour, Vinod Ravi, Shreyaskumar Patel, Robert S. Benjamin, Joseph Ludwig, Cynthia Herzog, Ravin Ratan, Neeta Somaiah, Anthony Conley, Richard Gorlick, Funda Meric-Bernstam, Vivek Subbiah
Summary: In this study, the outcomes of patients with ultrarare sarcomas in Phase 1 trials were assessed. The results showed that the median overall survival of ultrarare sarcomas was similar to common sarcomas, but the objective response rate to treatment was higher. Genomic selection played a significant role in identifying molecular subsets likely to benefit from targeted therapy in Phase 1 trials.
CLINICAL CANCER RESEARCH
(2023)
Article
Oncology
Joseph W. Kim, Rana R. McKay, Marc R. Radke, Shilin Zhao, Mary-Ellen Taplin, Nancy B. Davis, Paul Monk, Leonard J. Appleman, Primo N. Lara, Ulka N. Vaishampayan, Jingsong Zhang, Asit K. Paul, Glenn Bubley, Eliezer M. Van Allen, Serhan Unlu, Ying Huang, Massimo Loda, Geoffrey I. Shapiro, Peter M. Glazer, Patricia M. LoRusso, S. Percy Ivy, Yu Shyr, Elizabeth M. Swisher, Daniel P. Petrylak
Summary: The study investigated the clinical outcomes of combining Cediranib with olaparib in patients with prostate cancer. The results showed that the combination improved radiographic progression-free survival in patients with metastatic castration-resistant prostate cancer compared to olaparib alone. However, it was also associated with a higher incidence of adverse events.
JOURNAL OF CLINICAL ONCOLOGY
(2023)
Review
Biotechnology & Applied Microbiology
Alexandre Andre B. A. da Costa, Dipanjan Chowdhury, Geoffrey I. Shapiro, Alan D. D'Andrea, Panagiotis A. Konstantinopoulos
Summary: Replication stress is a major cause of genomic instability and a vulnerability of cancer cells. Inhibiting kinases such as ATR, CHK1, WEE1, and MYT1 can target this vulnerability. In addition, inhibiting the DNA damage response can elicit an immune response. Therefore, several inhibitors are being evaluated in clinical trials to overcome therapeutic resistance and promote antitumor immunity by targeting replication stress.
NATURE REVIEWS DRUG DISCOVERY
(2023)
Article
Oncology
Funda Meric-Bernstam, James M. Ford, Peter J. O'Dwyer, Geoffrey I. Shapiro, Lisa M. McShane, Boris Freidlin, Roisin E. O'Cearbhaill, Suzanne George, Julia Glade-Bender, Gary H. Lyman, James Tricoli, David Patton, Stanley R. Hamilton, Robert J. Gray, Douglas S. Hawkins, Bhanumati Ramineni, Keith T. Flaherty, Petros Grivas, Timothy A. Yap, Jordan Berlin, James H. Doroshow, Lyndsay N. Harris, Jeffrey A. Moscow
Summary: In the past decade, there have been multiple trials to determine the effectiveness of treating cancer based on specific genomic alterations. However, most patients do not respond to single-agent therapies targeting a single alteration, and drug resistance often develops. To address this, the NCI has developed NCI-ComboMATCH, a study to explore genomically-directed combination therapies and overcome drug resistance.
CLINICAL CANCER RESEARCH
(2023)
Article
Immunology
Lestat R. Ali, Ana C. Garrido-Castro, Patrick J. Lenehan, Naima Bollenrucher, Courtney T. Stump, Michael Dougan, Shom Goel, Geoffrey I. Shapiro, Sara M. Tolaney, Stephanie K. Dougan
Summary: The authors analyzed blood and tumors from breast and ovarian cancer patients treated with PD-1 blockade and CDK4/6 inhibition using single-cell RNA-sequencing and TCR tracking. They found that both therapies enhance T cell effector function and memory. In mouse models of melanoma and breast cancer, the augmentation of the antitumor memory pool by ribociclib boosts the efficacy of subsequent PD-1 blockade, suggesting sequential therapy as a potentially safe and synergistic strategy in patients.
JOURNAL OF EXPERIMENTAL MEDICINE
(2023)
Article
Oncology
Nami Yamashita, Yoshihiro Morimoto, Atsushi Fushimi, Rehan Ahmad, Atrayee Bhattacharya, Tatsuaki Daimon, Naoki Haratake, Yuka Inoue, Satoshi Ishikawa, Masaaki Yamamoto, Tsuyoshi Hata, Sayuri Akiyoshi, Qiang Hu, Tao Liu, Henry Withers, Song Liu, Geoffrey I. Shapiro, Tomoharu Yoshizumi, Mark D. Long, Donald Kufe
Summary: In certain cancer cells, the chromatin remodeling complex SWI/SNF PBAF's subunit polybromo-1 (PBRM1) drives DNA damage resistance and immune evasion through unclear mechanisms. This study found that MUC1-C is necessary for PBRM1 expression in triple-negative breast cancer (TNBC) cells, and the two proteins form a nuclear complex. Transcriptional and chromatin accessibility analysis showed that MUC1-C and PBRM1 increase the expression of STAT1 and IRF1 by enhancing chromatin accessibility on their respective genes, as well as other genes involved in DNA damage resistance and immune evasion.
MOLECULAR CANCER RESEARCH
(2023)
Article
Oncology
Christian Kollmannsberger, Herbert Hurwitz, Lyudmila Bazhenova, Byoung Chul Cho, David Hong, Keunchil Park, Karen L. Reckamp, Sunil Sharma, Hirak Der-Torossian, James G. Christensen, Demiana Faltaos, Diane Potvin, Vanessa Tassell, Richard Chao, Geoffrey Shapiro
Summary: This phase I study determined the maximum tolerated dose, recommended phase II dose, and safety profile of glesatinib in patients with advanced or unresectable solid tumors. The study found that glesatinib had antitumor activity in patients with tumors harboring overexpression or amplification of MET and AXL, as well as MET-activating mutations or rearrangements. Based on the clinical activity, safety, and pharmacokinetic data, SDD 750 mg twice daily was selected as the preferred formulation and dose of glesatinib.
Article
Oncology
Meghan J. Mooradian, James M. Cleary, Anita Giobbie-Hurder, Lancia N. F. Darville, Aparna Parikh, Elizabeth I. Buchbinder, Justine V. Cohen, Donald P. Lawrence, Geoffrey I. Shapiro, Harold Keer, Helen X. X. Chen, Susan Percy Ivy, Keiran S. M. Smalley, John M. Koomen, Ryan J. Sullivan
Summary: This study showed that the combination of HSP90 inhibitor AT13387 with dabrafenib and trametinib was safe and led to modest disease control in heavily pretreated patients with BRAF V600E/K-mutant solid tumors. Further research is needed to identify tumor types and resistance mechanisms that are most sensitive to this approach.
Article
Oncology
David S. Hong, Michael Postow, Bartosz Chmielowski, Ryan Sullivan, Amita Patnaik, Ezra E. W. Cohen, Geoffrey Shapiro, Conor Steuer, Martin Gutierrez, Heather Yeckes-Rodin, Robert Ilaria Jr, Brenda O'Connell, Joanna Peng, Guangbin Peng, Nora Zizlsperger, Anthony Tolcher, Jedd D. Wolchok
Summary: This study evaluated the safety and tolerability of a new antitumor drug, IPI-549, and found that it has good antitumor activity when used in combination with PD-1/PD-L1 inhibitors, and with minimal side effects. Therefore, doses of 30 and 40 mg of IPI-549 were chosen for the next phase of the study.
CLINICAL CANCER RESEARCH
(2023)
Article
Multidisciplinary Sciences
James J. Harding, Sarina A. Piha-Paul, Ronak H. H. Shah, Jessica J. Murphy, James M. Cleary, Geoffrey I. Shapiro, David I. Quinn, Irene Brana, Victor Moreno, Mitesh Borad, Sherene Loi, Iben Spanggaard, Haeseong Park, James M. Ford, Monica Arnedos, Salomon M. Stemmer, Christelle de la Fouchardiere, Christos Fountzilas, Jie Zhang, Daniel DiPrimeo, Casey Savin, S. Duygu Selcuklu, Michael F. Berger, Lisa D. Eli, Funda Meric-Bernstam, Komal Jhaveri, David B. Solit, Ghassan K. Abou-Alfa
Summary: In patients with biliary tract cancer, HER2 alterations correlate with poor prognosis. A phase II clinical trial showed that the tyrosine kinase inhibitor neratinib has some efficacy in treating advanced biliary tract cancers with HER2-mutation positive. The objective response rate to neratinib was 16% (95% CI 4.5-36.1%).
NATURE COMMUNICATIONS
(2023)
Article
Oncology
Blessie Elizabeth Nelson, Jason Roszik, Filip Janku, David S. Hong, Shumei Kato, Aung Naing, Sarina Piha-Paul, Siqing Fu, Apostolia Tsimberidou, Maria Cabanillas, Naifa Lamki Busaidy, Milind Javle, Lauren Averett Byers, John V. Heymach, Funda Meric-Bernstam, Vivek Subbiah
Summary: Combined BRAF + MEK inhibition has been approved by FDA for solid tumors with BRAF V600E mutation, except for colorectal cancer. However, besides MAPK-mediated resistance, there are other mechanisms of resistance, such as activation of CRAF, ARAF, MET, P13K/AKT/mTOR pathway. In the VEM-PLUS study, a pooled analysis of four phase one studies was conducted to evaluate the safety and efficacy of vemurafenib monotherapy and combination regimens in advanced solid tumors with BRAF V600 mutations. The results showed that compared to vemurafenib monotherapy, combinations of vemurafenib with targeted therapies or cytotoxic chemotherapy did not significantly improve overall survival (OS) or progression-free survival (PFS) of patients with BRAF V600E-mutant solid tumors.
NPJ PRECISION ONCOLOGY
(2023)
Review
Oncology
Omar Alhalabi, Roman Groisberg, Ralph Zinner, Andrew W. Hahn, Aung Naing, Shizhen Zhang, Apostolia M. Tsimberidou, Jordi Rodon, Siqing Fu, Timothy A. Yap, David S. Hong, Ming Sun, Yunfang Jiang, Shubham Pant, Amishi Y. Shah, Amado Zurita, Nizar M. Tannir, Raghunandan Vikram, Jason Roszik, Funda Meric-Bernstam, Vivek Subbiah
Summary: Pre-clinically, the mTORC1/2 inhibitor sapanisertib restored sensitivity to platinums and enhanced paclitaxel-induced cancer cell killing. In a clinical trial, patients with mTOR pathway aberrant tumors were treated with sapanisertib, carboplatin, and paclitaxel. The study showed that the combination therapy had manageable safety and preliminary antitumor activity in advanced malignancies with mTOR pathway alterations.
NPJ PRECISION ONCOLOGY
(2023)
Review
Oncology
Christian Rolfo, Elisa Giovannetti, Pablo Martinez, Shannon McCue, Aung Naing
Summary: Toll-like receptors (TLRs) play a crucial role in the immune system and have the potential to be targeted for cancer therapies. TLRs are involved in the defense against microbes and induce immune responses. By combining TLR agonists with immune checkpoint inhibitors, it is possible to convert cold tumors into hot tumors, improving treatment outcomes. Imiquimod is a TLR7 agonist approved for antiviral and skin cancer treatments, and several other TLR adjuvants are being used in vaccines. Many TLR agonists are currently being developed as monotherapy or in combination with immune checkpoint inhibitors for solid tumors.
NPJ PRECISION ONCOLOGY
(2023)
Article
Multidisciplinary Sciences
Zahra Talebi, Dominique A. Garrison, Eric D. Eisenmann, Kalindi Parmar, Geoffrey I. Shapiro, Michelle A. Rudek, Alex Sparreboom, Yan Jin
Summary: A rapid, sensitive, and simple UHPLC-MS/MS method was developed and validated for the determination of the PARP inhibitor talazoparib in mouse plasma. The method showed good accuracy and reproducibility, making it suitable for pharmacokinetic studies.