Roisin McMorrow, Henriette S de Bruijn, Stefania Farina, Ruben J L van Ardenne, Ivo Que, Pier G Mastroberardino, Dominic J Robinson, Laura Mezzanotte, Clemens W G M Löwik
{"title":"Combination of Bremachlorin PDT and immune checkpoint inhibitor anti-PD-1 shows response in murine immunological T-cell high and T-cell low PDAC models.","authors":"Roisin McMorrow, Henriette S de Bruijn, Stefania Farina, Ruben J L van Ardenne, Ivo Que, Pier G Mastroberardino, Dominic J Robinson, Laura Mezzanotte, Clemens W G M Löwik","doi":"10.1158/1535-7163.MCT-23-0733","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-23-0733","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is one of the most challenging types of cancer with little or no response to immune checkpoint inhibitors (ICIs). Photodynamic therapy (PDT) has been shown to ablate tumors and induce an immune response. In our study, we investigated the effect of photodynamic therapy (PDT), using the photosensitizer Bremachlorin, in its ability to reduce tumor burden and to sensitize immunologically T-cell high and T-cell low murine PDAC tumors to the ICI that blocks programmed cell death-1 (PD-1) immune checkpoint. In addition, we monitored the effect on survival and investigated if there was a response in PDT-treated and non PDT-treated distant tumors. Our results showed that Bremachlorin PDT induces direct tumor killing which increased survival in both 'hot' T-cell high and 'cold' T-cell low PDAC tumors and that it can make the T-cell high tumors more sensitive to ICI blocking PD-1. We found that T-cell high tumor bearing mice had an overall greater response to therapy than T-cell low tumor bearing mice. One mouse with T-cell high tumors exhibited complete tumor regression in both the treated and non-treated distant tumor 90 days after treatment. These results indicate that combining immune checkpoint inhibitors (ICIs) with Bremachlorin PDT could be a promising therapeutic intervention for enhancing PDAC's response to therapy.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142864854","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xiuqin Lou, Qibing Zhou, Ying Yin, Cheng Zhou, Yan Shen
{"title":"Correction: Inhibition of the Met Receptor Tyrosine Kinase Signaling Enhances the Chemosensitivity of Glioma Cell Lines to CDDP Through Activation of p38 MAPK Pathway.","authors":"Xiuqin Lou, Qibing Zhou, Ying Yin, Cheng Zhou, Yan Shen","doi":"10.1158/1535-7163.MCT-24-0974","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0974","url":null,"abstract":"","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"OF1"},"PeriodicalIF":5.3,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142846860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Victoria M Valvo, Qiang Zhang, Long Jiang, Erin A Holcomb, Ashley N Pearson, Anna G Edmunds, Hailey G Faulkner, Jadyn G James, Akshay Tate, Amanda K Huber, Zhuwen Wang, Yupei Guo, David Karnak, Leslie A Parsels, Joshua D Parsels, Yu L Lei, Alnawaz Rehemtulla, Heng Lin, Eileen S Carpenter, Daniel R Wahl, Vaibhav Sahai, Theodore S Lawrence, Michael D Green, Meredith A Morgan
{"title":"Olaparib and Radiotherapy Induce Type I Interferon- and CD8+ T Cell-Dependent Sensitization to Immunotherapy in Pancreatic Cancer.","authors":"Victoria M Valvo, Qiang Zhang, Long Jiang, Erin A Holcomb, Ashley N Pearson, Anna G Edmunds, Hailey G Faulkner, Jadyn G James, Akshay Tate, Amanda K Huber, Zhuwen Wang, Yupei Guo, David Karnak, Leslie A Parsels, Joshua D Parsels, Yu L Lei, Alnawaz Rehemtulla, Heng Lin, Eileen S Carpenter, Daniel R Wahl, Vaibhav Sahai, Theodore S Lawrence, Michael D Green, Meredith A Morgan","doi":"10.1158/1535-7163.MCT-24-0210","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0210","url":null,"abstract":"<p><p>PARP inhibitors sensitize pancreatic ductal adenocarcinoma (PDAC) to radiation by inducing DNA damage and replication stress. These mechanisms also have the potential to enhance radiation-induced type I interferon (T1IFN)-mediated antitumoral immune responses. We hypothesized that the PARP inhibitor olaparib would also potentiate radiation-induced T1IFN to promote antitumor immune responses and sensitization of otherwise resistant PDAC to immunotherapy. To test this hypothesis, we assessed the effects of olaparib and radiation on T1IFN production and sensitivity to αPD-L1 immunotherapy, as well as on the tumor microenvironment by single-cell RNA sequencing. We found that olaparib enhanced T1IFN production after radiation and had superior therapeutic efficacy in immunocompetent models. Olaparib and radiation treatment sensitized PDAC tumors to αPD-L1, resulting in decreased tumor burden and a 33% complete response rate. Combination treatment provided durable immune responses as shown by tumor rejection upon tumor rechallenge of previously cured mice. Furthermore, single-cell RNA sequencing analysis revealed that combination treatment induced an immunogenic tumor microenvironment characterized by interferon (IFN) responses in both PDAC and myeloid cell populations, macrophage polarization, and increased CD8+ terminal effector T-cell frequency and activity, findings which were confirmed by IHC and flow cytometry. Furthermore, CD8+ T cells and T1IFN signaling were required for therapeutic efficacy as host depletion of CD8+ T cells or the T1IFN receptor diminished treatment responses. Overall, our results indicate that olaparib enhances radiation-induced T1IFN-mediated immune signaling and subsequently an adaptive immune response, thus sensitizing pancreatic cancer to αPD-L1 therapy, supporting an ongoing clinical trial of this therapy in patients with PDAC.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"OF1-OF16"},"PeriodicalIF":5.3,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142837771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kimberley S Samkoe, Hira Shahzad Sardar, Jason R Gunn, Jonathan Thomas Elliott, Sally Mansur, Joachim Feldwisch, Brian W Pogue, Konstantinos Linos, Keith D Paulsen, Eric R Henderson
{"title":"First-in-human Study of ABY-029, a Novel Fluorescent Peptide that Targets Epidermal Growth Factor Receptor, Applied to Soft-Tissue Sarcomas.","authors":"Kimberley S Samkoe, Hira Shahzad Sardar, Jason R Gunn, Jonathan Thomas Elliott, Sally Mansur, Joachim Feldwisch, Brian W Pogue, Konstantinos Linos, Keith D Paulsen, Eric R Henderson","doi":"10.1158/1535-7163.MCT-24-0378","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0378","url":null,"abstract":"<p><p>ABY-029, an anti-epidermal growth factor receptor (EGFR) Affibody® molecule conjugated to IRDye 800CW, recently underwent first-in-human testing in soft-tissue sarcoma (STS). FDA Exploratory Investigational New Drug status was obtained for the Phase 0 clinical trial in which study objectives were to determine whether biological variance ratio (BVR) of 10 was achievable, fluorescence intensity correlated with EGFR expression, and doses were well tolerated. Patients (N=12) with STS were recruited based on positive EGFR immunohistochemical staining of diagnostic biopsies. ABY-029 was administered at micro- (30 nanomole, n=3), medium (90 nanomole, n=3), or high dose (171 nanomole, n=6), 1-3 hours prior to surgery. Following tumor resection, ex vivo tissue was imaged to determine mean fluorescence intensity (MFI), BVR, and other contrast measures. EGFR expression was correlated with immunohistochemistry. For micro-, medium, and high doses, mean BVR (SD) in cross-sectional slices were 4 (4), 10 (6), and 7 (8), respectively, for the whole tumor region and 6 (5), 13 (11), and 8 (6), respectively, for pathology-confirmed regions-of-interest. Strong linear correlations were found between all ABY-029 contrast metrics and total EGFR (r≥0.86, p<0.029) in cross-sectional tissue slices, and MFI and EGFR percent area (r=0.63, p<0.0001) in excised region-of-interest tissue sections. No ABY-029 related adverse events were observed. When administered above the microdose, ABY-029 demonstrated high correlation to EGFR expression and contrast values that were encouraging for translation to clinical practice. Contrast was similar to those observed with antibody agents, but with substantially reduced imaging-to-resection time, and no drug-related adverse events.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142837757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ken Akao, Tatsuhiro Sato, Emi Mishiro-Sato, Satomi Mukai, Farhana Ishrat Ghani, Lisa Kondo-Ida, Kazuyoshi Imaizumi, Yoshitaka Sekido
{"title":"TEAD-independent cell growth of Hippo-inactive mesothelioma cells: Unveiling resistance to TEAD inhibitor K-975 through MYC signaling activation.","authors":"Ken Akao, Tatsuhiro Sato, Emi Mishiro-Sato, Satomi Mukai, Farhana Ishrat Ghani, Lisa Kondo-Ida, Kazuyoshi Imaizumi, Yoshitaka Sekido","doi":"10.1158/1535-7163.MCT-24-0308","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0308","url":null,"abstract":"<p><p>Inactivation of the Hippo tumor suppressive pathway is frequently observed in mesothelioma, which leads to the activation of YAP and TAZ (YAP/TAZ) transcriptional coactivators. YAP/TAZ form complexes with TEAD family members, DNA-binding proteins, to activate transcription, which promotes cancer cell growth and proliferation. Recently developed TEAD inhibitors exhibit antitumor activity by inhibiting the formation of the transcription complex through binding to TEAD; however, the antitumor activity of TEAD inhibitors against mesothelioma remains to be fully elucidated. Here, we show that the TEAD inhibitor K-975 acts as a pan-TEAD inhibitor and selectively inhibits the binding of TEAD-binding proteins, especially YAP/TAZ, in mesothelioma cells. In studies using a panel of mesothelioma cell lines, K-975 showed a significant growth inhibitory effect on Hippo-inactivated mesothelioma cells, but some of these cell lines exhibited primary resistance to K-975. Differential gene expression analysis revealed that cells resistant to K-975 exhibited activation of MYC signaling in the presence of K-975, and cells overexpressed with MYC showed strong drug resistance, both in vitro and in vivo. Our study revealed the features of a subset of mesothelioma cells that proliferate in a TEAD-independent manner and provides important insights for the successful development of therapeutic strategies for mesothelioma with Hippo pathway inactivation.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142837777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"All-trans retinoic acid sensitizes epithelial ovarian cancer to PARP inhibition after exposure to cisplatin.","authors":"Bingjie Mei, Junyang Li, Dengfeng Wang, Lu Feng, Jianming Huang, Guonan Zhang","doi":"10.1158/1535-7163.MCT-24-0140","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0140","url":null,"abstract":"<p><p>Epithelial ovarian cancer (EOC) is the most lethal of gynecologic malignancies. The standard-of-care treatment for EOC is platinum-based chemotherapy such as cisplatin. Notably, Platinum-based chemotherapy induces resistance of EOC to poly (ADP-ribose) polymerase (PARP) inhibition. However, therapeutic approaches targeting PARP inhibitors (PARPi) resistance remain to be explored. Here, we show that all-trans retinoic acid (ATRA) reduces PARPi resistance-associated EOC cells induced by cisplatin (CDDP) treatment. Clinically applicable ATRA suppressed the outgrowth of CDDP-treated EOC cells both in vitro and in vivo. Moreover, a CDDP treatment followed by niraparib maintenance therapy in combination with ATRA improved the survival of EOC-bearing mice. These phenotypes correlated with PARPi resistant EOC signature, which consists of elevated expression of ALDH1A1, NAMPT, PARP1 and Chk1, as well as elevated NAD+ level-mediated high activity of ALDH1A1 and PARP1. Mechanistically, ATRA down-regulates the expression of these genes and level of intracellular NAD+. Our results suggest that ATRA in conjunction with PARPi represents a promising maintenance therapeutic strategy for EOC.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142829431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lawrence B Snyder, Taavi K Neklesa, Ryan R Willard, Deborah A Gordon, Jennifer Pizzano, Nicholas Vitale, Kaitlynn Robling, Madeline A Dorso, Walid Moghrabi, Sean Landrette, Richard Gedrich, Sang Hyun Lee, Ian C A Taylor, John G Houston
{"title":"Preclinical Evaluation of Bavdegalutamide (ARV-110), a Novel PROteolysis TArgeting Chimera Androgen Receptor Degrader.","authors":"Lawrence B Snyder, Taavi K Neklesa, Ryan R Willard, Deborah A Gordon, Jennifer Pizzano, Nicholas Vitale, Kaitlynn Robling, Madeline A Dorso, Walid Moghrabi, Sean Landrette, Richard Gedrich, Sang Hyun Lee, Ian C A Taylor, John G Houston","doi":"10.1158/1535-7163.MCT-23-0655","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-23-0655","url":null,"abstract":"<p><p>Androgen receptor (AR) signaling is the principal driver of prostate cancer, and drugs that target this pathway (e.g., abiraterone and enzalutamide) are standard treatments for metastatic hormone-sensitive prostate cancer and metastatic castration-resistant prostate cancer (mCRPC). However, continual evolution during prostate cancer progression can result in AR alterations (e.g., mutation, amplification, splicing) that can cause tumors to become resistant to these therapies. Bavdegalutamide (ARV-110) is a PROteolysis TArgeting Chimera (PROTAC®) protein degrader that recruits the cereblon-containing E3 ubiquitin ligase to direct the polyubiquitination and subsequent proteasomal degradation of AR. Bavdegalutamide selectively degrades wild-type AR and most clinically relevant mutants with low nanomolar potency. The superiority of the degradation mechanism of action is demonstrated by bavdegalutamide's higher activity relative to the AR antagonist enzalutamide in cell-based systems that assess effects on prostate-specific antigen (PSA) synthesis, prostate cancer cell proliferation, and induction of apoptosis. In an AR-expressing patient-derived xenograft mouse model, bavdegalutamide showed substantial AR degradation and greater tumor growth inhibition compared with enzalutamide. Bavdegalutamide also showed robust tumor growth inhibition in enzalutamide- and abiraterone-resistant prostate cancer animal models and enhanced activity in combination with abiraterone. These promising preclinical data supported clinical development of bavdegalutamide as a potential treatment for patients with prostate cancer. Bavdegalutamide was the first PROTAC protein degrader to enter human clinical trials, specifically in patients with mCRPC in a phase 1/2 study (NCT03888612).</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142818473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
James T Paget, Joseph A Ward, Andrew R McKean, David C Mansfield, Martin McLaughlin, Joan N Kyula-Currie, Henry G Smith, Victoria Roulstone, Chunhei Li, You Zhou, Thomas Hardiman, Anita Grigoriadis, Devin O'Brien Coon, Sheeba Irshad, Alan A Melcher, Kevin J Harrington, Aadil Khan
{"title":"CXCL12-targeted immunomodulatory gene therapy reduces radiation-induced fibrosis in healthy tissues.","authors":"James T Paget, Joseph A Ward, Andrew R McKean, David C Mansfield, Martin McLaughlin, Joan N Kyula-Currie, Henry G Smith, Victoria Roulstone, Chunhei Li, You Zhou, Thomas Hardiman, Anita Grigoriadis, Devin O'Brien Coon, Sheeba Irshad, Alan A Melcher, Kevin J Harrington, Aadil Khan","doi":"10.1158/1535-7163.MCT-23-0872","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-23-0872","url":null,"abstract":"<p><p>Radiation-induced fibrosis (RIF) is a progressive pathology deleteriously impacting cancer survivorship. CXCL12 is an immune-stromal signal implicated in fibrosis and innate response. We hypothesised that modulation of CXCL12 would phenotypically mitigate RIF. CXCL12 expression was characterised in a rodent model of RIF and its expression modulated by the intravascular delivery of lentiviral vectors encoding small hairpin RNA to silence (LVShCXCL12) or overexpress (LVOeCXCL12) CXCL12. Multi-modal fibrotic outcomes were quantified, flow cytometry and Y-chromosome lineage-tracking studies performed to examine cellular recruitment and activation post-radiotherapy (post-RT). Whole-tissue RNA-seq was used to examine matrisomal response. MATBIII tumours were engrafted within tissues with differing levels of CXCL12 expression and tumoral response to RT evaluated. CXCL12 was upregulated in irradiated fibroblasts demonstrating DNA-damage post-RT and led to the recruitment of CD68+ macrophages. Silencing Cxcl12 with LVShCXCL12 demonstrated reduced RIF phenotype as a result of decreased macrophage recruitment. Transcriptomic profiling identified osteopontin (SPP1) as being highly differentially expressed in LVShCXCL12-treated tissues. Tumours growing in tissues devoid of CXCL12 expression responded better following RT due to reductions in peri-tumoural fibrosis as a result of decreased CXCL12 and OPN expression at the tumour/normal tissue interface. This was also associated with greater CD8+ T cell infiltration in tumours with less fibrosis. Antibody-mediated OPN blockade slowed tumour growth by increased intra-tumoral CD8+ T cell activation. The CXCL12/OPN axis is an important node of immune/matrisomal cross-talk in the development of fibrosis. Therapeutic manipulation of this axis may offer greater anti-tumour efficacy whilst also reducing adverse effects.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yogesh K Chutake, Michele F Mayo, Nancy Dumont, Jessica Filiatrault, Susanne B Breitkopf, Patricia Cho, Dapeng Chen, Vaishali S Dixit, William R Proctor, Eric W Kuhn, Sarah Bollinger Martinez, Alice A McDonald, Jianfeng Qi, Kan-Nian Hu, Rahul Karnik, Joseph D Growney, Kirti Sharma, Stefanie S Schalm, Ashwin M Gollerkeri, Nello Mainolfi, Juliet A Williams, Matthew M Weiss
{"title":"KT-253, A Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy Than MDM2 Small Molecule Inhibitors.","authors":"Yogesh K Chutake, Michele F Mayo, Nancy Dumont, Jessica Filiatrault, Susanne B Breitkopf, Patricia Cho, Dapeng Chen, Vaishali S Dixit, William R Proctor, Eric W Kuhn, Sarah Bollinger Martinez, Alice A McDonald, Jianfeng Qi, Kan-Nian Hu, Rahul Karnik, Joseph D Growney, Kirti Sharma, Stefanie S Schalm, Ashwin M Gollerkeri, Nello Mainolfi, Juliet A Williams, Matthew M Weiss","doi":"10.1158/1535-7163.MCT-24-0306","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0306","url":null,"abstract":"<p><p>Murine double minute 2 (MDM2) is an E3 ligase that inhibits the tumor suppressor protein p53. Clinical trials employing small-molecule MDM2/p53 interaction inhibitors (SMIs) have demonstrated limited activity, underscoring an unmet need for a better approach to target MDM2. KT 253 is a highly potent and selective heterobifunctional degrader that overcomes the MDM2 feedback loop seen with SMIs and induces apoptosis in a range of hematologic and solid tumor lines. A single intravenous dose of KT 253 triggered rapid apoptosis and sustained tumor regression in p53 wild-type acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) xenograft models. Additionally, a single intravenous dose of KT 253 in combination with standard-of-care (SoC) venetoclax, overcame venetoclax resistance in an AML xenograft model. The data herein define the therapeutic potential of KT-253 and support its clinical development in a range of hematologic and solid p53 wild-type (WT) malignancies, as a monotherapy and in combination with SoC agents.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Melissa L Johnson, Beni B Wolf, Judy S Wang, Alexander Philipovskiy, Geoffrey I Shapiro, Bruno Bockorny, Wei Guo, Jinshan Shen, Kai Yu Jen, MaryBeth LeRose, Tamieka Lauz Hunter, Mahesh Padval, Oleg Schmidt-Kittler, Namrata Bhatia, Sarita Dubey, Julia Suchomel, Johanna C Bendell, Shekeab Jauhari, Jennifer Eng-Wong, Jessica J Lin
{"title":"First results of migoprotafib, a potent and highly selective Src homology-2 domain-containing phosphatase 2 (SHP2) inhibitor in patients with advanced solid tumors.","authors":"Melissa L Johnson, Beni B Wolf, Judy S Wang, Alexander Philipovskiy, Geoffrey I Shapiro, Bruno Bockorny, Wei Guo, Jinshan Shen, Kai Yu Jen, MaryBeth LeRose, Tamieka Lauz Hunter, Mahesh Padval, Oleg Schmidt-Kittler, Namrata Bhatia, Sarita Dubey, Julia Suchomel, Johanna C Bendell, Shekeab Jauhari, Jennifer Eng-Wong, Jessica J Lin","doi":"10.1158/1535-7163.MCT-24-0466","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0466","url":null,"abstract":"<p><p>Src homology-2 domain-containing phosphatase 2 (SHP2) promotes RAS-MAPK signaling and tumorigenesis and is a promising therapeutic target for multiple solid tumors. Migoprotafib is a potent and highly selective SHP2 inhibitor designed for the treatment of RAS-MAPK driven cancers, particularly in combination with other targeted agents. Here we report first-in-human study results of single agent migoprotafib in advanced solid tumor patients. We conducted a phase 1a, open-label, multi-center, dose-escalation and expansion study in adult patients with locally advanced or metastatic solid tumors. The key objectives were to evaluate safety, pharmacokinetics, pharmacodynamics (peripheral blood pERK) and preliminary anti-tumor activity. Fifty-six heavily pre-treated patients were treated with migoprotafib (10-150 mg QD). Migoprotafib had a rapid absorption rate (~0.5-2 hours) with dose-dependent increases in exposure and pathway modulation (pERK changes). The maximum tolerated dose was 100 mg and the recommended phase 2 dose (RP2D) was 60 mg daily (QD) based on safety, pharmacokinetics (PK), pharmacodynamics, and anti-tumor activity. Migoprotafib was generally well tolerated with the most frequent adverse events of diarrhea, peripheral edema, dyspnea, anemia, constipation, fatigue, AST increase and platelet count decrease. Stable disease was observed in 10 patients (18%). Migoprotafib had predictable, dose-dependent PK with an effective half-life that supports QD dosing and demonstrated promising safety, tolerability, and clinical activity at the RP2D. Further clinical testing of migoprotafib in combination with other targeted agents is warranted.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142780608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}