Article
Oncology
Diana Canals Hernaez, Michael R. Hughes, Yicong Li, Ilaria Mainero Rocca, Pamela Dean, Julyanne Brassard, Erin M. Bell, Ismael Samudio, Anne-Marie Mes-Masson, Yoshiki Narimatsu, Henrik Clausen, Ola Blixt, Calvin D. Roskelley, Kelly M. McNagny
Summary: Podocalyxin is a key cell surface sialomucin that plays a role in tumor metastasis and poor prognosis, with a novel antibody PODO447 showing specificity in targeting tumor cells. PODO447 functions effectively in killing various tumor cell lines and targeting human tumors in xenograft models.
FRONTIERS IN ONCOLOGY
(2022)
Article
Pharmacology & Pharmacy
Shujun Dong, Ian Nessler, Anna Kopp, Baron Rubahamya, Greg M. M. Thurber
Summary: Preclinical in vivo studies are crucial for drug development, but translation to the clinic can be challenging, especially for biologics with unique mechanisms of action. Animal models may allow intolerable doses or screen out potential drugs, highlighting the need for mechanistic simulations to guide dosing strategies and compound selection. Predictive models based on drug disposition insights can help identify promising clinical compounds early in the drug development process.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Oncology
Katherine K. Slemmons, Sanjit Mukherjee, Paul Meltzer, James W. Purcell, Lee J. Helman
Summary: LRRC15-directed ADCs show promising efficacy in inhibiting growth of high LRRC15 expressing OS cell lines, with potential to sensitize insensitive OS cells after re-expression. LRRC15-PNU demonstrates high cure rates in OS xenograft models, suggesting a new avenue for OS treatment.
PEDIATRIC BLOOD & CANCER
(2021)
Review
Biochemistry & Molecular Biology
Kenji Nakano
Summary: HER2-targeted therapies have been investigated for various malignant diseases, including osteosarcoma. However, an effective HER2-targeted therapy for osteosarcoma has not been established. The antibody-drug conjugate T-DXd showed promising efficacy in HER2-positive malignant diseases, but not in HER2-positive osteosarcoma.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Oncology
Yi Zhang, Silvia K. Tacheva-Grigorova, Janette Sutton, Zea Melton, Yvonne S. L. Mak, Cecilia Lay, Bryan A. Smith, Tao Sai, Thomas Van Blarcom, Barbra J. Sasu, Siler H. Panowski
Summary: The purpose of this study was to explore the role of DLL3 in SCLC and evaluate the safety and efficacy of DLL3 CAR T cells. The results showed that DLL3 CAR T cells had a strong anti-tumor effect and no significant tissue damage was observed in the brain and pituitary. Therefore, this study provides a basis for further evaluation of the potential role of DLL3 CAR T cells in the treatment of SCLC.
CLINICAL CANCER RESEARCH
(2023)
Article
Pharmacology & Pharmacy
Arnold Lee
Summary: Loncastuximab tesirine is an antibody-drug conjugate developed for the treatment of B cell lymphomas, currently approved in the US for specific types of lymphoma treatment while being researched for treatments of other types of lymphoma.
Article
Oncology
Yezhe Cheng, Xiaoxi Yuan, Qiang Tian, Xiuying Huang, Yang Chen, Yuzhi Pu, Hu Long, Mingyu Xu, Yafei Ji, Jia Xie, Yuping Tan, Xi Zhao, Hongmei Song
Summary: The study aimed to enhance the intratumoral accumulation of an antibody-drug conjugate (ADC) and reduce its off-target toxicity. SKB264, a novel ADC targeting trophoblast antigen 2 (TROP2), showed promising pharmacologic profiles in vitro and in vivo, with stronger targeting effect and better antitumor activity compared to IMMU-132. These findings suggest the potential therapeutic efficacy of SKB264 for TROP2-positive tumors.
FRONTIERS IN ONCOLOGY
(2022)
Article
Medicine, Research & Experimental
Josefa Dela Cruz Chuh, MaryAnn Go, Yvonne Chen, Jun Guo, Hanine Rafidi, Danielle Mandikian, Yonglian Sun, Zhonghua Lin, Kellen Schneider, Pamela Zhang, Rajesh Vij, Danielle Sharpnack, Pamela Chan, Cecile de la Cruz, Jack Sadowsky, Dhaya Seshasayee, James T. Koerber, Thomas H. Pillow, Gail D. Phillips, Rebecca K. Rowntree, C. Andrew Boswell, Katherine R. Kozak, Andrew G. Polson, Paul Polakis, Shang-Fan Yu, Peter S. Dragovich, Nicholas J. Agard
Summary: Early success with brentuximab vedotin in treating classical Hodgkin lymphoma led to the development of multiple MMAE antibody-drug conjugates, but most of these have not been successful in clinical trials. This study describes the development of second-generation therapeutic ADCs targeting Ly6E, with a focus on using DNA-damaging agents to improve durability of response. The new ADCs showed promising preclinical efficacy in driving tumor regression and reducing the likelihood of resistance compared to traditional MMAE-based conjugates.
Article
Chemistry, Multidisciplinary
Liujuan Zhou, Fan Yang, Zhaoshuai Bai, Xiaohui Zhou, Zhihai Zhang, Zhihang Li, Junyuan Gong, Junqi Yu, Liqiang Pan, Chan Cao, James J. Chou
Summary: One challenge in improving clinical outcomes of antibody drug conjugates (ADCs) is overcoming cancer resistance to the antibody and/or drug components of ADCs. In this study, a self-assembled left-handed DNA (L-DNA) oligonucleotide was used to link combinatory single-domain antibodies and toxin payloads for tunable and adaptive delivery of ADCs. The newly constructed ADCs with L-DNA scaffold showed promising properties in vitro and in vivo. This suggests that the L-DNA based modular ADC (MADC) platform is a viable option for generating therapeutic ADCs and expanding the therapeutic window.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Oncology
Min Yuen Teo, Jonathan E. Rosenberg
Summary: Nectin-4 serves as the target for enfortumab vedotin, with its gene expression varying significantly across different molecular subtypes and playing a crucial role in the efficacy of enfortumab vedotin.
CLINICAL CANCER RESEARCH
(2021)
Article
Pharmacology & Pharmacy
Eun-Jeong Jeon, Ju-Hee Han, Youjin Seo, Eun Mi Koh, Kang-Hyun Han, Kyunghwa Hwang, Kyung Jin Jung
Summary: Antibody-drug conjugates (ADCs) are a promising cancer treatment that selectively bind target antigens without the side effects of traditional chemotherapies. This study optimized methods for quantifying a specific ADC, T-DM1, in rats. Four analytical methods were optimized and used to analyze samples in order to evaluate the quantification, pharmacokinetics, and immunogenicity of T-DM1. This research establishes a systematic bioanalysis of ADCs with validated assays, providing a foundation for future investigations on the efficacy and safety of ADC development.
Article
Oncology
Keiko Tokuchi, Takuya Maeda, Shinya Kitamura, Teruki Yanagi, Hideyuki Ujiie
Summary: The prognosis for advanced Extramammary Paget's disease (EMPD) is usually poor. HER2-targeted antibody-drug conjugates (ADCs) have shown promising results in treating HER2-positive breast cancers. This study found that HER2-targeted ADCs can significantly regress EMPD tumors in a patient-derived xenograft (PDX) model with pathogenic ERBB2 mutations.
Article
Pharmacology & Pharmacy
Ophelia Yin, Yuan Xiong, Seiko Endo, Kazutaka Yoshihara, Tushar Garimella, Malaz AbuTarif, Russ Wada, Frank LaCreta
Summary: This study characterized the pharmacokinetics of Trastuzumab deruxtecan in patients with HER2-positive breast cancer or other solid tumor malignancies. Results showed no significant differences in steady-state exposure of the drug in different patient populations, suggesting that dose adjustment based on specific patient characteristics is not necessary.
CLINICAL PHARMACOLOGY & THERAPEUTICS
(2021)
Article
Oncology
Yifei Wang, Xiangjun Tian, Wendong Zhang, Zhongting Zhang, Rossana Lazcano, Pooja Hingorani, Michael E. Roth, Jonathan D. Gill, Douglas J. Harrison, Zhaohui Xu, Sylvester Jusu, Sankaranarayanan Kannan, Jing Wang, Alexander J. Lazar, Eric J. Earley, Stephen W. Erickson, Tara Gelb, Philip Huxley, Johanna Lahdenranta, Gemma Mudd, Raushan T. Kurmasheva, Peter J. Houghton, Malcolm A. Smith, Edward A. Kolb, Richard Gorlick
Summary: This study describes an integrated proteomic and transcriptomic surfaceome profiling approach to identify cell-surface proteins that are highly expressed in osteosarcoma. Three targets, MT1-MMP, CD276, and MRC2, were validated as overexpressed in osteosarcoma. Testing a MT1-MMP-targeted Bicycle toxin conjugate, BT1769, in osteosarcoma patient-derived xenograft models showed encouraging antitumor activity, high affinity for its target, and a favorable pharmacokinetic profile. This confirms the hypothesis that the approach identifies novel targets with significant therapeutic potential in osteosarcoma.
MOLECULAR CANCER THERAPEUTICS
(2022)
Review
Pharmacology & Pharmacy
Pornsak Sriamornsak, Crispin R. Dass
Summary: This review explores the current status and limitations of chitosan research in the field of cardiovascular health, specifically atherosclerosis. It also discusses the applications and future directions of chitosan nanoparticles in this field.
Article
Oncology
Todd M. Cooper, Michael J. Absalon, Todd A. Alonzo, Robert B. Gerbing, Kasey J. Leger, Betsy A. Hirsch, Jessica Pollard, Bassem I. Razzouk, Richard Aplenc, E. Anders Kolb
JOURNAL OF CLINICAL ONCOLOGY
(2020)
Article
Oncology
Kelly D. Getz, Lillian Sung, Todd A. Alonzo, Kasey J. Leger, Robert B. Gerbing, Jessica A. Pollard, Todd Cooper, E. Anders Kolb, Alan S. Gamis, Bonnie Ky, Richard Aplenc
JOURNAL OF CLINICAL ONCOLOGY
(2020)
Article
Oncology
Grace Nevil, Michael Roth, Jonathan Gill, Wendong Zhang, Beverly Teicher, Stephen W. Erickson, Gregory Gatto, Malcom Smith, E. Anders Kolb, Richard Gorlick
Summary: Research showed that eltrombopag did not significantly improve event-free survival (EFS) in 6 out of 6 models at moderate doses. However, at high doses, eltrombopag significantly prolonged EFS in 2 out of 2 models, with a small effect size. All tested models demonstrated progressive disease. While eltrombopag did not effectively inhibit osteosarcoma growth, it also did not stimulate tumor growth, suggesting it may be safely investigated as a supportive care agent to enhance platelet recovery post chemotherapy.
PEDIATRIC HEMATOLOGY AND ONCOLOGY
(2021)
Article
Oncology
Pooja Hingorani, Michael E. Roth, Yifei Wang, Wendong Zhang, Jonathan B. Gill, Douglas J. Harrison, Beverly Teicher, Stephen Erickson, Gregory Gatto, Malcolm A. Smith, Edward A. Kolb, Richard Gorlick
Summary: The membrane protein LRRC15 is expressed in solid tumors, including osteosarcoma. The antibody-drug conjugate ABBV-085, targeting LRRC15, showed antitumor activity in osteosarcoma PDX models, inhibiting tumor growth in six out of seven models and improving event-free survival in five models. These findings suggest LRRC15 as a promising target for clinical trials in osteosarcoma patients.
MOLECULAR CANCER THERAPEUTICS
(2021)
Article
Oncology
Nathan M. Kendsersky, Jarrett Lindsay, E. Anders Kolb, Malcolm A. Smith, Beverly A. Teicher, Stephen W. Erickson, Eric J. Earley, Yael P. Mosse, Daniel Martinez, Jennifer Pogoriler, Kateryna Krytska, Khushbu Patel, David Groff, Matthew Tsang, Samson Ghilu, Yifei Wang, Steven Seaman, Yang Feng, Brad St Croix, Richard Gorlick, Raushan Kurmasheva, Peter J. Houghton, John M. Maris
Summary: The study demonstrates significant antitumor activity of the B7-H3-targeting antibody-drug conjugate in pediatric solid tumor PDX models, showing a positive response across various cancer types.
CLINICAL CANCER RESEARCH
(2021)
Article
Oncology
Mareike Rasche, Martin Zimmermann, Emma Steidel, Todd Alonzo, Richard Aplenc, Jean-Pierre Bourquin, Heidrun Boztug, Todd Cooper, Alan S. Gamis, Robert B. Gerbing, Iveta Janotova, Jan-Henning Klusmann, Thomas Lehrnbecher, Nora Muehlegger, Nils V. Neuhoff, Naghmeh Niktoreh, Lucie Sramkova, Jan Stary, Katharina Waack, Christiane Walter, Ursula Creutzig, Michael Dworzak, Gertjan Kaspers, Edward Anders Kolb, Dirk Reinhardt
Summary: This study evaluated survival, response, and prognostic variables following relapse in children with acute myeloid leukemia (AML). Initial high-risk features and early relapse were found to predict post-relapse survival, while full hematopoietic recovery did not necessarily correlate with better survival outcomes. The data suggest the need for post-relapse risk stratification in future studies.
Article
Oncology
Gilles Vassal, Peter J. Houghton, Stefan M. Pfister, Malcolm A. Smith, Huib N. Caron, Xiao-Nan Li, David J. Shields, Olaf Witt, Jan J. Molenaar, Sara Colombetti, Julia Schueler, Lou F. Stancato
Summary: Cancer remains the leading cause of disease-related death in children, with limited curative treatment options for those experiencing relapses of malignant solid tumors. Lack of molecular genetic data and appropriate patient-derived models are hindering preclinical drug testing efforts. Recommendations based on existing experiences are provided to guide preclinical pediatric cancer research and inform clinical development.
MOLECULAR CANCER THERAPEUTICS
(2021)
Review
Oncology
Jonathan Gill, Richard Gorlick
Summary: Osteosarcoma, the most common primary bone cancer in children and young adults, presents challenges in treatment due to its rarity and molecular heterogeneity. Collaborative efforts in biological discoveries, technologies, and therapeutic approaches are expected to advance osteosarcoma treatment and improve patient outcomes. The increasing feasibility of molecular profiling, along with the creation of robust model systems and large tissue banks, has enhanced understanding of osteosarcoma biology.
NATURE REVIEWS CLINICAL ONCOLOGY
(2021)
Article
Oncology
Anderson B. Collier, Mark D. Krailo, Ha M. Dang, Steven G. DuBois, Douglas S. Hawkins, Mark L. Bernstein, Lisa R. Bomgaars, Damon R. Reed, Richard G. Gorlick, Katherine A. Janeway
Summary: Analysis of seven Children's Oncology Group phase 2 trials for patients with relapsed/progressive solid tumors showed a 6-month event-free survival (EFS) of 12.7% for relapsed/progressive Ewing sarcoma patients, indicating poor outcomes. Despite docetaxel achieving its protocol-specified radiographic response rate, its EFS was similar to other agents, suggesting that a higher radiographic response rate may not lead to superior disease control. This EFS benchmark could be used as an additional endpoint in trials for recurrent Ewing sarcoma.
PEDIATRIC BLOOD & CANCER
(2021)
Article
Oncology
Raushan T. Kurmasheva, Stephen W. Erickson, Ruolan Han, Beverly A. Teicher, Malcolm A. Smith, Michael Roth, Richard Gorlick, Peter J. Houghton
Summary: SP-2577, an inhibitor of LSD1, showed limited activity against pediatric sarcoma models, with modest growth inhibition observed in Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma xenografts under the evaluated dose and schedule.
PEDIATRIC BLOOD & CANCER
(2021)
Article
Cell Biology
Xin Zhou, Allyson Beilter, Zhaohui Xu, Ruli Gao, Shunbin Xiong, Adriana Paulucci-Holthauzen, Guillermina Lozano, Benoit de Crombrugghe, Richard Gorlick
Summary: This study identified chondrocytes as an additional source for mesenchymal progenitor cells (MPCs) and showed that Wnt/ss-catenin pathway discretely regulates the development from chondrocytes to C-MPC and subsequently from C-MPC to osteoblasts. Furthermore, the study unveiled a previously unrecognized functional link between ss-catenin and p53, with p53 playing a negative role in MPC osteogenic differentiation induced by Wnt/ss-catenin signaling.
CELL DEATH & DISEASE
(2021)
Article
Oncology
Qing Yang, Jiemiao Hu, Zhiliang Jia, Qi Wang, Jing Wang, Long Hoang Dao, Wendong Zhang, Sheng Zhang, Xueqing Xia, Richard Gorlick, Shulin Li
Summary: This study proposes a new cell therapy for treating osteosarcoma. By introducing a specific protein into peripheral blood mononuclear cells, tumor growth can be effectively inhibited without observable toxicity.
CLINICAL CANCER RESEARCH
(2022)
Correction
Medicine, General & Internal
Hannah C. Beird, Stefan S. Bielack, Adrienne M. Flanagan, Jonathan Gill, Dominique Heymann, Katherine A. Janeway, J. Andrew Livingston, Ryan D. Roberts, Sandra J. Strauss, Richard Gorlick
NATURE REVIEWS DISEASE PRIMERS
(2022)
Article
Medicine, General & Internal
Hannah C. Beird, Stefan S. Bielack, Adrianne M. Flanagan, Jonathan Gill, Dominique Heymann, Katherine A. Janeway, J. Andrew Livingston, Ryan D. Roberts, Sandra J. Strauss, Richard Gorlick
Summary: Osteosarcoma is the most common primary malignant bone tumor with a bimodal incidence peaking at 18 and 60 years of age. It is more common in males and is driven by genetic factors related to bone formation leading to malignant progression and metastasis. Screening is currently focused on high-risk groups, and the prognosis for patients with metastatic disease remains poor.
NATURE REVIEWS DISEASE PRIMERS
(2022)
Article
Biochemistry & Molecular Biology
Jiayi Sun, Wing-Yuk Chow, Gufeng Xu, M. John Hicks, Manjula Nakka, Jianhe Shen, Patrick Kwok Shing M. Ng, Aaron Taylor, Alexander E. Yu, Jason A. Farrar, Donald Barkauskas, Richard M. Gorlick, Jaime M. Guidry Auvil, Daniela Gerhard, Paul Meltzer, Rudy Guerra, Tsz-Kwong C. Man, Ching Lau, TARGET Osteosarcoma Consortium
Summary: Osteosarcoma is a primary malignant bone tumor that commonly metastasizes to the lungs. Altered FAS expression due to DNA methylation has been explored as a mechanism in cancer cells. Analysis revealed high variability in methylation of CpG sites that correlated with FAS mRNA expression. Treatment with demethylating agent 5-azacytidine restored FAS protein expression and reduced metastasis in osteosarcoma cells.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)