bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Anticancer Efficacy of KRASG12C Inhibitors Is Potentiated by PAK4 Inhibitor KPT9274 in Preclinical Models of KRASG12C-Mutant Pancreatic and Lung Cancers
Authors: Khan Husain Yar , Nagasaka Misako , Aboukameel Amro , Alkhalili Osama , Uddin Md. Hafiz , Bannoura Sahar F. , Mzannar Yousef , Azar Ibrahim , Beal Eliza W. , Tobon Miguel E. , Kim Steve H. , Beydoun Rafic , Baloglu Erkan , Senapedis William , El-Rayes Bassel F. , Philip Philip A. , Mohammad Ramzi M. , Shields Anthony F. , Al Hallak Mohammed Najeeb , Azmi Asfar S.
Published: December 2023

Abstract
KRASG12C inhibitors, such as sotorasib and adagrasib, have revolutionized cancer treatment for patients with KRASG12C-mutant tumors. However, patients receiving these agents as monotherapy often develop drug resistance. To address this issue, we evaluated the combination of the PAK4 inhibitor KPT9274 and KRASG12C inhibitors in preclinical models of pancreatic ductal adenocarcinoma (PDAC) and non–small cell lung cancer (NSCLC). PAK4 is a hub molecule that links several major signaling pathways and is known for its tumorigenic role in mutant Ras–driven cancers. We found that cancer cells resistant to KRASG12C inhibitor were sensitive to KPT9274-induced growth inhibition. Furthermore, KPT9274 synergized with sotorasib and adagrasib to inhibit the growth of KRASG12C-mutant cancer cells and reduce their clonogenic potential. Mechanistically, this combination suppressed cell growth signaling and downregulated cell-cycle markers. In a PDAC cell line–derived xenograft (CDX) model, the combination of a suboptimal dose of KPT9274 with sotorasib significantly reduced the tumor burden (P= 0.002). Similarly, potent antitumor efficacy was observed in an NSCLC CDX model, in which KPT9274, given as maintenance therapy, prevented tumor relapse following the discontinuation of sotorasib treatment (P= 0.0001). Moreover, the combination of KPT9274 and sotorasib enhances survival. In conclusion, this is the first study to demonstrate that KRASG12C inhibitors can synergize with the PAK4 inhibitor KPT9274 and combining KRASG12C inhibitors with KPT9274 can lead to remarkably enhanced antitumor activity and survival benefits, providing a novel combination therapy for patients with cancer who do not respond or develop resistance to KRASG12C inhibitor treatment.
Data from Radiotherapy-induced Immune Response Enhanced by Selective HDAC6 Inhibition
Authors: Noonepalle Satish Kumar R. , Grindrod Scott , Aghdam Nima , Li Xintang , Gracia-Hernandez Maria , Zevallos-Delgado Christian , Jung Mira , Villagra Alejandro , Dritschilo Anatoly
Published: December 2023

Abstract
Radiotherapy is a curative cancer treatment modality that imparts damage to cellular DNA, induces immunogenic cell death, and activates antitumor immunity. Despite the radiotherapy-induced direct antitumor effect seen within the treated volume, accumulating evidence indicates activation of innate antitumor immunity. Acute proinflammatory responses mediated by anticancer M1 macrophages are observed in the immediate aftermath following radiotherapy. However, after a few days, these M1 macrophages are converted to anti-inflammatory and pro-cancer M2 phenotype, leading to cancer resistance and underlying potential tumor relapse. Histone deacetylase 6 (HDAC6) plays a crucial role in regulating macrophage polarization and innate immune responses. Here, we report targeting HDAC6 function with a novel selective inhibitor (SP-2-225) as a potential therapeutic candidate for combination therapy with radiotherapy. This resulted in decreased tumor growth and enhanced M1/M2 ratio of infiltrating macrophages within tumors. These observations support the use of selective HDAC6 inhibitors to improve antitumor immune responses and prevent tumor relapse after radiotherapy.
Data from RYZ101 (Ac-225 DOTATATE) Opportunity beyond Gastroenteropancreatic Neuroendocrine Tumors: Preclinical Efficacy in Small-Cell Lung Cancer
Authors: Han Guangzhou , Hwang Eunmi , Lin Fanching , Clift Renee , Kim Daniel , Guest Matt , Bischoff Eric , Moran Susan , Li Gary
Published: December 2023

Abstract
Overexpression of somatostatin receptors (SSTR), particularly SSTR2, is found in gastroenteropancreatic neuroendocrine tumors (GEP-NET), and subsets of other solid tumors such as small-cell lung cancer (SCLC). SCLC accounts for approximately 13% to 15% of lung cancer and lacks effective therapeutic options. IHC analysis indicates that up to 50% of SCLC tumors are SSTR2-positive, with a substantial subset showing high and homogenous expression. Peptide receptor radionuclide therapy with radiolabeled somatostatin analogue, Lu-177 DOTATATE, has been approved for GEP-NETs. Different strategies aimed at improving outcomes, such as the use of alpha-emitting radioisotopes, are currently being investigated. RYZ101 (Ac-225 DOTATATE) is comprised of the alpha-emitting radioisotope actinium-225, chemical chelator DOTA, and octreotate (TATE), a somatostatin analogue. In the cell-based competitive radioligand binding assay, RAYZ-10001-La (lanthanum surrogate for RYZ101) showed high binding affinity (Ki = 0.057 nmol/L) to human SSTR2 and >600-fold selectivity against other SSTR subtypes. RAYZ-10001-La exhibited efficient internalization to SSTR2-positive cells. In multiple SSTR2-expressing SCLC xenograft models, single-dose intravenous RYZ101 3 μCi (0.111 MBq) or 4 μCi (0.148 MBq) significantly inhibited tumor growth, with deeper responses, including sustained regression, observed in the models with higher SSTR2 levels. The antitumor effect was further enhanced when RYZ101 was combined with carboplatin and etoposide at clinically relevant doses. In summary, RYZ101 is a highly potent, alpha-emitting radiopharmaceutical agent, and preclinical data demonstrate the potential of RYZ101 for the treatment of patients with SSTR-positive cancers.
Data from Pro-905, a Novel Purine Antimetabolite, Combines with Glutamine Amidotransferase Inhibition to Suppress Growth of Malignant Peripheral Nerve Sheath Tumor
Authors: Lemberg Kathryn M. , Ali Eunus S. , Krecmerova Marcela , Aguilar Joanna Marie H. , Alt Jesse , Peters Diane E. , Zhao Liang , Wu Ying , Nuha Naziba , Asara John M. , Staedtke Verena , Pratilas Christine A. , Majer Pavel , Rais Rana , Ben-Sahra Issam , Slusher Barbara S.
Published: December 2023

Abstract
Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive soft-tissue sarcomas that arise from neural tissues and carry a poor prognosis. Previously, we found that the glutamine amidotransferase inhibitor JHU395 partially impeded tumor growth in preclinical models of MPNST. JHU395 inhibits de novo purine synthesis in human MPNST cells and murine tumors with partial decreases in purine monophosphates. On the basis of prior studies showing enhanced efficacy when glutamine amidotransferase inhibition was combined with the antimetabolite 6-mercaptopurine (6-MP), we hypothesized that such a combination would be efficacious in MPNST. Given the known toxicity associated with 6-MP, we set out to develop a more efficient and well-tolerated drug that targets the purine salvage pathway. Here, we report the discovery of Pro-905, a phosphoramidate protide that delivered the active nucleotide antimetabolite thioguanosine monophosphate (TGMP) to tumors over 2.5 times better than equimolar 6-MP. Pro-905 effectively prevented the incorporation of purine salvage substrates into nucleic acids and inhibited colony formation of human MPNST cells in a dose-dependent manner. In addition, Pro-905 inhibited MPNST growth and was well-tolerated in both human patient-derived xenograft (PDX) and murine flank MPNST models. When combined with JHU395, Pro-905 enhanced the colony formation inhibitory potency of JHU395 in human MPNST cells and augmented the antitumor efficacy of JHU395 in mice. In summary, the dual inhibition of the de novo and purine salvage pathways in preclinical models may safely be used to enhance therapeutic efficacy against MPNST.
Abstract A010: Gloriosine induces cell cycle arrest by autophagic cell death through negative regulation of YAP transcriptional activity in non-small cell lung cancer. Gloriosine is a potent alkaloid derivative having potent anti cancer activity
Authors: Dey Biswajit , Goel Bharat , Chatterjee Essha , Singh Hoshiyar , Jain Shreyans , Guru Santosh Kumar
Published: December 2023

Autophagy plays a dual role in the development and advancement of various tumor. YAP, a component of the Hippo pathway, is known to be associated with autophagy. This study aims to explore the relationship between YAP and autophagy with respect to cell death pathway in lung cancer. Non-small cell lung cancer (NSCLC) accounts for most of the cancer death among all types of lung cancer. Here, we explored antiproliferative and antimigratory effect of compound gloriosine on A549 cells through Autophagy/Hippo signalling pathway. In the present study, we demonstrated that gloriosine inhibits cell viability of A549 cell lines (at 100nM concentration of 24 hours of treatment) in vitro by inducing autophagy with very low toxicity to normal breast cells MCF10A (>1000nM). At 100nM concentration gloriosine led to G2/M cell cycle arrest after an hour of treatment in A549 cell lines. Furthermore, it affects (at 25nM) Hippo signalling through retention of YAP protein into cytoplasm and inhibiting YAP localization into nucleus, suppressing the expression of downstream target gene. Inhibition of YAP localization supresses AKT/mTOR pathway which ultimately leads to activation of autophagy dependent cell death. Spheroid formation assay reveals gloriosine treatment can inhibits tumor relapse and reduce the size of the spheroid of A549 cells in a dose dependent manner. This molecule also inhibits lung cancer tumor growth in nude mice at 27% and 64% with dose of 1mg/kg and 5mg/kg body weight respectively.  These current results suggest that gloriosine has the potential to serve as a new anticancer drug candidate.

Citation Format: Biswajit Dey, Bharat Goel, Essha Chatterjee, Hoshiyar Singh, Shreyans Jain, Santosh Kumar Guru. Gloriosine induces cell cycle arrest by autophagic cell death through negative regulation of YAP transcriptional activity in non-small cell lung cancer. Gloriosine is a potent alkaloid derivative having potent anti cancer activity [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A010.
Abstract A021: Screening of novel therapeutic markers for ovarian cancer stem cells
Authors: Choi Dong Kyu , Min Sang Hyun
Published: December 2023

Drug resistance in epithelial ovarian cancer is reportedly attributed to the existence of cancer stem cells, because in most cancers, CSCs still remain after chemotherapy. To overcome this limitation, novel therapeutic strategies are required to prevent cancer recurrence and chemotherapy-resistant cancers by targeting cancer stem cells. We screened an FDA-approved compound and clinical libraries, and found several small molecule drugs that target ovarian CSCs. These drugs decreased sphere formation, viability, and proliferation, and induced apoptosis in ovarian CSCs. Since these drugs harbor target proteins, we investigated the expression of the target proteins in ovarian CSC and found the increased level of the protein expression and new therapeutic markers of ovarian CSCs. Downregulation of these genes reduced the stem-cell-like properties of ovarianCSCs. Expressions of these three genes are negatively correlated with the survival rate of patient groups. In combination therapy with chemo agents, synergistic ect was shown in inhibiting the viability and proliferation of ovarian CSCs.  Our results suggested that these may be potential therapeutic drugs for preventing ovarian cancer recurrence.

Citation Format: Dong Kyu Choi, Sang Hyun Min. Screening of novel therapeutic markers for ovarian cancer stem cells [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A021.
Abstract A058: Investigating the molecular role of BRD9 in synovial sarcoma
Authors: Topal Salih , Dominici Claudia , Collins Michael , Lahr David L , Zhou Qianhe , Uzan Flore , Mayhew David , Adam Ammar , Garbitt-Amaral Victoria , Antonakos Brandon , Mikse Oliver , Ahmad Hafiz , Parikh Salonee , Lin Mei Yun , Wu Hsin-Jung , Sandoval Gabriel , Soares Luis M. M. , Muwanguzi Jordana , Chen Huawei , Yang Zhaoxia , Lowe Jason T. , Netherton Matt , Zawadzke Laura , Voigt Johannes , Huang Liyue , Ruppel Sabine , Chan Ho Man , Kruger Ryan , Millan David S. , Innis Scott , Bellon Steven F.
Published: December 2023

Bromodomain-containing protein 9 (BRD9) represents a potential selective vulnerability for tumors with specific alterations in the Brahma-associated factor (BAF) chromatin remodeling complex.  One example of such a modification is the incorporation of the SS18-SSX fusion into BAF complexes.  This alteration is a hallmark of synovial sarcoma, and thought to drive tumorigenesis. As BRD9 is a subunit unique to ncBAF, tumors that depend on ncBAF for survival may be susceptible to BRD9 degradation.  Accordingly, selective BRD9 degradation is a potential therapeutic approach to treat such diseases. Previous work has shown that loss of BRD9 causes cell and tumor proliferation defects (Brien et al. 2018, Michel et al. 2018).  To explore the mechanism by which degradation of BRD9 causes cell and tumor proliferation defects in synovial sarcoma, we utilized a multi-omic approach using RNA-seq, ATAC-seq, and ChIP-seq data to understand the molecular impact of loss of BRD9 on relevant cell lines and animal model tumors. ChIP-seq revealed genome-wide colocalization of BRD9 and Myc on chromatin, and BRD9 degradation can lead to MYC loss at the majority of these co-bound regions.  Genes commonly regulated in synovial cell lines treated with a BRD9 degrader in vitro and/or in vivo are enriched in MYC target genes, ribosome biogenesis genes and cell cycle genes. Furthermore, the genes commonly downregulated in synovial cell lines treated with a BRD9 degrader have notable MYC binding at their promoter regions. Therefore, we propose that these downregulated genes might be potential MYC targets, specifically in synovial sarcoma, and that downregulation leads to observed proliferation defects.

Citation Format: Salih Topal, Claudia Dominici, Michael Collins, David L Lahr, Qianhe Zhou, Flore Uzan, David Mayhew, Ammar Adam, Victoria Garbitt-Amaral, Brandon Antonakos, Oliver Mikse, Hafiz Ahmad, Salonee Parikh, Mei Yun Lin, Hsin-Jung Wu, Gabriel Sandoval, Luis M. M. Soares, Jordana Muwanguzi, Huawei Chen, Zhaoxia Yang, Jason T. Lowe, Matt Netherton, Laura Zawadzke, Johannes Voigt, Liyue Huang, Sabine Ruppel, Ho Man Chan, Ryan Kruger, David S. Millan, Scott Innis, Steven F. Bellon. Investigating the molecular role of BRD9 in synovial sarcoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A058.
Abstract A063: Epigenetic regulation of Neuregulin 1 promotes breast cancer progression associated to hyperglycemia
Authors: Lee Changhu , Kim Min , Park Chanho , Jo Woobeen , Park Jiyoung
Published: December 2023

Hyperglycemia is a risk factor for breast cancer-related morbidity and mortality. Hyperglycemia induces Neuregulin 1 (Nrg1) overexpression in breast cancer, which subsequently promotes tumor progression. However, molecular mechanisms underlying hyperglycemia-induced Nrg1 overexpression remain poorly understood. Here, we show that hyperglycemia causes active histone modifications at the Nrg1 enhancer, forming enhanceosome complexes where recombination signal binding protein for immunoglobulin kappa J region (RBPJ), E1A binding protein p300 (P300), and SET domain containing 1A (SETD1A) are recruited to upregulate Nrg1 expression. Deletions in RBPJ-binding sites causes hyperglycemia-controlled Nrg1 levels to be downregulated, resulting in decreased tumor growth in vitro and in vivo. Mice with modest-temporary hyperglycemia, induced by low-dose short-exposure streptozotocin, display accelerated tumor growth and lapatinib resistance, whereas combining lapatinib with N-[N-(3, 5-difluorophenacetyl)-l-alanyl]-S42 phenylglycine t-butyl ester (DAPT) ameliorates tumor growth under these modest hyperglycemic conditions by inhibiting NOTCH and EGFR superfamilies. NOTCH activity is correlated with NRG1 levels, and high NRG1 levels predicts poor outcomes, particularly in HER2-positive breast cancer patients. Our findings highlight the hyperglycemia-linked epigenetic modulation of NRG1 as a potential therapeutic strategy for treating breast cancer patients with diabetes.

Citation Format: Changhu Lee, Min Kim, Chanho Park, Woobeen Jo, Jiyoung Park. Epigenetic regulation of Neuregulin 1 promotes breast cancer progression associated to hyperglycemia [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A063.
Abstract A101: Novel KRAS inhibitors suppress MAPK pathway signalling and display potent anti-proliferative activity across a broad range of KRAS mutant cell lines
Authors: Bhamra Inder , Mason Helen , Woodcock Simon , Anderson Katie , Kelly James , Haydon Grace , La Montagna Manuela , Brierley Megan , Bishop Emma , Keeler Ross , Ryan James , Jackson Paula , Aylott Helen , Ho Kelvin , Leng Daniel , Jones Clifford , Phillips Caroline
Published: December 2023

KRAS is the most frequently mutated oncogene across different cancer types. Redx Pharma are developing novel, orally bioavailable, small molecule inhibitors of KRAS. These compounds display activity against a broad spectrum of the most frequently occurring KRAS mutations whilst maintaining selectivity over NRAS and HRAS protein isoforms. Isoform selective multi-KRAS inhibitors were identified using biochemical SOS1-independent nucleotide exchange assays (NEA) and validated by surface plasmon resonance (SPR) spectroscopy. Compounds of interest were the further triaged using relevant cancer cell lines for inhibition of phospho-ERK (pERK) and anti-proliferative effects both in 2 and 3-dimensional assay formats. KRAS selective inhibitors retaining activity across a spectrum of mutations were identified, these compounds exhibit picomolar affinity for KRAS, translating into low nanomolar antiproliferative activity. As further confirmation of MAPK pathway inhibition, treatment of relevant cancer cell lines with Redx compounds resulted in suppression of DUSP6 and SPTY4 gene expression. Cellular washout experiments indicated sustained inhibition of pERK post washout of compounds consistent with high affinity compounds with extended residency time at KRAS. Optimisation towards KRAS inhibitors suitable for clinical evaluation is ongoing.

Citation Format: Inder Bhamra, Helen Mason, Simon Woodcock, Katie Anderson, James Kelly, Grace Haydon, Manuela La Montagna, Megan Brierley, Emma Bishop, Ross Keeler, James Ryan, Paula Jackson, Helen Aylott, Kelvin Ho, Daniel Leng, Clifford Jones, Caroline Phillips. Novel KRAS inhibitors suppress MAPK pathway signalling and display potent anti-proliferative activity across a broad range of KRAS mutant cell lines [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A101.
Abstract A159: Mechanisms of uveal melanoma sensitivity to velcrin treatment and SLFN12-mediated cancer cell death
Authors: Kotynkova Kristyna , Andersen Sawyer , Garvie Colin , Wu Xiaoyun , Lee Sooncheol , McGaunn Joseph , Kaplan Bethany , Tseng Moony , Cherniack Andrew D , Meyerson Matthew , Greulich Heidi
Published: December 2023

Velcrins are a novel class of compounds that kill cancer cells expressing elevated levels of PDE3A and SLFN12. These compounds induce PDE3A-SLFN12 heterotetramer complex formation, resulting in upregulation of the RNase activity of SLFN12. SLFN12 cleaves tRNA-Leu-TAA, which leads to the inhibition of global translation and, consequently, apoptosis of cells expressing sufficient levels of both proteins. Uveal melanoma, a type of melanoma that occurs in the eye, is genomically distinct from cutaneous melanoma. Whereas mutations of BRAF, NRAS, KRAS, and HRAS are common in cutaneous melanoma, uveal melanomas instead harbor mutually exclusive mutations of the G protein alpha subunits, GNAQ and GNA11. Around 50% of patients will develop metastatic disease with a very poor prognosis. Immunotherapy is not effective for these patients, nor are any targeted therapies available beyond tebentafusp, with an ORR of 9%.  We found that a subset of uveal melanoma cell lines expresses elevated levels of PDE3A and SLFN12 and is sensitive to velcrin treatment.  We are currently assessing whether velcrin treatment of these cell lines results in cleavage of tRNA-Leu-TAA, inhibition of protein synthesis, and tumor cell death, with the goal of developing a new treatment for uveal melanoma patients.   To further understand the mechanism of velcrin-induced cancer cell death, we hypothesized that the primary function of PDE3A in the PDE3A-SLFN12 heterotetramer is the dimerization of SLFN12. Based on our cryo-EM structure of the PDE3A-SLFN12 complex, we identified SLFN12 I131 as a critical residue in the SLFN12 homodimer interface. We showed that a SLFN12 I131Q mutation disrupts SLFN12 dimerization and prevents tRNA-Leu-TAA cleavage in vitro. We have also shown that wild-type SLFN12 can dimerize independently of PDE3A or PDE3A-velcrin interactions. In PDE3A-depleted cells, the overexpression of wild-type SLFN12 results in cell death. We are currently testing SLFN12 I131Q for its ability to initiate SLFN12-dependent cytotoxicity in cells. Additionally, we are preparing different SLFN12 constructs that would allow us to induce chemical dimerization of SLFN12 and we plan to test if the forced dimerization of SLFN12 rescues its RNase activity and results in cell death.

Citation Format: Kristyna Kotynkova, Sawyer Andersen, Colin Garvie, Xiaoyun Wu, Sooncheol Lee, Joseph McGaunn, Bethany Kaplan, Moony Tseng, Andrew D Cherniack, Matthew Meyerson, Heidi Greulich. Mechanisms of uveal melanoma sensitivity to velcrin treatment and SLFN12-mediated cancer cell death [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A159.
Abstract A165: FGFR alterations in pediatric cancers: Opportunity for targeted therapy
Authors: Li Ivan , Huo Yuchen , Li Gary , Zage Peter
Published: December 2023

Introduction: The Fibroblast Growth Factor Receptor (FGFR) family consists of four members, FGFR1–4, and is involved in regulating cell proliferation, survival, and differentiation. FGFR alterations, such as fusions, mutations and amplification, have been found in multiple adult cancers, for which several FGFR inhibitors are in clinical development. Although cancer is a leading cause of death in children, the understanding of genetic causes of pediatric cancers is urgently lacking and the progress in developing targeted therapy in children significantly lags that in adults. This study aimed to uncover the FGFR alterations in pediatric cancers and provide preclinical rationale for FGFR inhibitors as potential therapy in children with cancer. 

Methods: The prevalence of FGFR alterations in pediatric cancers such as neuroblastoma (NB) , gliomas and sarcomas was calculated based on systematic queries of multiple cancer databases that house real-world molecular profiling data. A pan-FGFR inhibitor, BGJ398, was used as a tool compound for FGFR inhibition. Effect of BGJ398 on cell proliferation was tested by Incucyte in a panel of 12 NB cell lines. Cell migration, survival and signaling pathway modulation were carried out in a subset of NB lines.

Results: The overall rates of genomic alterations (fusions, mutations and amplification) of FGFR1, 2, 3 and 4 in pediatric cancers are 0.5%, 0.1%, 1.1% and 0.8%, respectively, with pediatric gliomas exhibiting higher rates in all subtypes. Although FGFR genomic alterations are rare (<0.1%) in neuroblastoma and rhabdoid sarcoma, overexpression of FGFR1-4 is observed in subsets of these tumors. In pediatric glioma, FGFR1, 2, 3 and 4 alterations are found in 1%, 1.6%, 2.1% and 0.9% tumor samples, respectively, and the mutation profile substantially differs from that of adult glioma. Dose-dependent inhibition of cell proliferation and migration, as well as induction of cell death, were achieved with BGJ398 treatment in a panel of NB cells, accompanied by inhibition of MAPK pathway and induction of apoptosis.

Conclusions: Adult and pediatric cancers share common mechanisms of FGFR activation, but differ in overall alteration rates and in relative abundance of specific aberrations. Preliminary preclinical data indicates the therapeutic potential of FGFR inhibitors in the treatment of certain pediatric cancers.

Citation Format: Ivan Li, Yuchen Huo, Gary Li, Peter Zage. FGFR alterations in pediatric cancers: Opportunity for targeted therapy [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A165.
Abstract A178: Therapeutic potential of a p14ARF minimal domain peptide in non-small cell lung cancer
Authors: Grobelny Anna L , Maggi Leonard B , Weber Jason D
Published: December 2023

Many current therapeutic efforts in cancer biology focus on inhibiting the function of aberrant oncogenes whose activities are known to increase proliferation and cell growth. Unfortunately, these efforts have had limited success in lung cancer, where the five-year survival rate remains unchanged. We sought a novel approach; rather than inhibiting oncogenes, we worked to reestablish the function of the p14ARF tumor suppressor in non-small cell lung cancer (NSCLC) to block tumor growth and proliferation. The p14ARF tumor suppressor is encoded by the CDKN2A gene and is the second most commonly mutated gene in NSCLC. p14ARF is known to play a fundamental role in preventing cancer progression by regulating senescence, apoptosis, and proliferation. Here, to determine the minimal functional domain of p14ARF, we generated a panel of p14ARF expression mutants, deleting various amino acids within the known functional and conserved domains of p14ARF. These mutants were then evaluated for their ability to function as wild type p14ARF. Through proliferative and transformative studies, we identified a 10-amino acid domain that is required for p14ARF function. New cell-penetrating peptide technology was employed to determine if these resides were sufficient to elicit antiproliferative effects on their own. We now show that this small region of ARF is capable of entering tumor cells when linked to a cell penetrating peptide. Moreover, this small cell penetrating ARF peptide retains all of ARF’s known tumor suppressor functions. Our findings provide evidence that small cell penetrating peptides are capable of inhibiting tumor cell growth and proliferation. These experiments also lay the foundation for more precise therapeutic peptide cancer treatments, ones that could be used to restore p14ARF tumor suppressor function.

Citation Format: Anna L Grobelny, Leonard B Maggi, Jason D Weber. Therapeutic potential of a p14ARF minimal domain peptide in non-small cell lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A178.
Abstract B013: Identification of a Notch transcriptomic signature for breast cancer
Authors: Braune Eike-Benjamin , Geist Felix , Tang Xiaojia , Kalari Krishna , Boughey Judy , Wang Liewei , Leon-Ferre Roberto A. , D’Assoro Antonino B. , Ingle James N. , Goetz Matthew P. , Wang Kang , Foukakis Theodoros , Seshire Anita , Wienke Dirk , Lendahl Urban
Published: December 2023

Background: Dysregulated Notch signalling contributes to breast cancer development and progression, but validated tools to measure the level of Notch signalling in breast cancer subtypes and in response to systemic therapy are largely lacking. A transcriptomic signature of Notch signalling would thus be warranted, and in this report, we have established such a classifier.

Methods: To generate the signature, we first identified Notch-regulated genes from six basal-like breast cancer cell lines subjected to elevated and reduced Notch signalling by culturing on immobilized Notch ligand Jagged1 or blockade of Notch by g-secretase inhibitors, respectively. From this cadre of Notch-regulated genes, we developed candidate transcriptomic signatures that were trained on a breast cancer patient dataset (the TCGA-BRCA cohort) and a broader breast cancer cell line cohort and sought to validate in independent data sets.

Results: An optimal 20-gene transcriptomic signature was selected. We validated the signature on two independent patient datasets (METABRIC and Oslo2) and it showed an improved coherence score and tumour specificity compared with previously published signatures. Furthermore, the signature score was particularly high for basal-like breast cancer, indicating an enhanced level of Notch signalling in this subtype. The signature score was increased after neoadjuvant treatment in the PROMIX and BEAUTY patient cohorts, and a lower signature score generally correlated with better clinical outcome.

Conclusions: The 20-gene transcriptional signature has the potential to better stratify patients and to evaluate the response of future Notch-based therapies for breast cancer.

Citation Format: Eike-Benjamin Braune, Felix Geist, Xiaojia Tang, Krishna Kalari, Judy Boughey, Liewei Wang, Roberto A. Leon-Ferre, Antonino B. D’Assoro, James N. Ingle, Matthew P. Goetz, Kang Wang, Theodoros Foukakis, Anita Seshire, Dirk Wienke, Urban Lendahl. Identification of a Notch transcriptomic signature for breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B013.
Abstract B015: Tumor fraction as a predictive factor of outcome of patients referred for oncology early phase clinical trials: Analysis of the STING precision medicine study
Authors: Belcaid Laila , Bayle Arnaud , Trin Kilian , Aldea Mihaela , Vasseur Damien , Sakkal Madona , Loriot Yohann , Hollebecque Antoine , Ponce Santiago , Italiano Antoine
Published: December 2023

Background The quantification of ctDNA shed by measuring tumor fraction (TF) has been associated with prognosis in solid tumors pts. However, whether TF can be also predictive of clinical benefit of systemic treatments in patients referred for early phase studies remain unknown.  

Methods: All consecutive adult pts with an advanced solid tumor referred to the Early Phase Trials Department of Gustave Roussy( Villejuif France) between December 2020 and December 2021 and enrolled in the  precision medicine study STING (NCT04932525, sponsor: Institut Gustave Roussy, Villejuif, France) were analyzed.  All pts underwent comprehensive genomic profiling with the 324-gene FoundationOne. TF was analyzed as a binary variable, indicating whether a specimen had TF ≥10% or TF <10%. Response to treatment was assessed as per RECIST criteria. Multivariate analysis included previously validated prognostic scores: the Royal Marsden Hospital (albumin, LDH, number of metastatic sites) and the GRIm (LDH, neutrophil/lymphocyte ratio (NLR), albumin) scores as well as their individual components.

Results: 947 patients entered the study. High TF was associated with significantly worse overall survival (OS) (HR:2.52 [CI95%: 2.06 - 3.08, p<0.001] independently of the RMH and GRIM scores as well as their individual components. 409 pts received a systemic treatment following ctDNA profiling (Immuno-oncology agent: 146 patients, non-IO: 254 patients)The treatment was investigational for 200 patients.  The most frequent tumor types were non-small cell lung cancer (n=85), prostate cancer (n=49), colorectal cancer (n=33). High TF was significantly associated with worse objective response/stable disease rate (37.8% vs 53.8%, p=0.006), PFS (2.1 vs 3.9 months, p<0.001) and OS (7.1 vs 18.6 months, p<0.001) .

Conclusions: Besides its prognostic value, TF is predictive of outcome on systemic therapy in patients referred for early phase studies. This parameter can be used for informed decision making for patients before participating in phase 1 trials.

Citation Format: Laila Belcaid, Arnaud Bayle, Kilian Trin, Mihaela Aldea, Damien Vasseur, Madona Sakkal, Yohann Loriot, Antoine Hollebecque, Santiago Ponce, Antoine Italiano. Tumor fraction as a predictive factor of outcome of patients referred for oncology early phase clinical trials: Analysis of the STING precision medicine study [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B015.
Abstract B022: Effects of RSO-021 on cytokine profiles of malignant pleural effusions from patients enrolled in the MITOPE phase 1/2 clinical trial
Authors: Messier Terri , Scotland Molly , Naumov George , Dulloo Sean , Fennell Dean , Cunniff Brian
Published: December 2023

Tumor cells generate increased levels of reactive oxygen species (ROS) that promote growth and survival through activation of redox dependent signaling pathways. To survive under increased ROS levels tumor cells, including mesotheliomas, must increase antioxidant expression, activity and reliance on critical ROS scavenging pathways, including the mitochondrial peroxiredoxin 3 (PRX3) system. PRX3 is a critical ROS scavenging enzyme localized to the mitochondrial matrix. Our group has characterized the mechanism of action of the PRX3 inhibitor and pro-oxidant therapeutic thiostrepton (TS). TS covalently crosslinks the peroxidatic and resolving cysteines of PRX3, leading to increased levels of mitochondrial ROS, resulting in tumor cell death. TS is the active pharmaceutical ingredient of RSO-021, a new covalent inhibitor of PRX3 currently being tested in the MITOPE phase 1/2 clinical trial in patients with malignant pleural effusion (MPE) due to advanced solid tumors or mesothelioma (NCT05278975). RSO-021 is administered locally to patients through an indwelling pleural catheter (IPC) weekly. TS targets PRX3 in both adherent tumor cells and in non-adherent immune cell populations in a dose-dependent manner when tested ex vivo. Using MPE drainages from patients enrolled in the MITOPE trial we evaluated cytokine levels pre and 24 and 168 - hours (7 days) post initial administration of RSO-021. Cytokines were measured in decellularized MPE drainages using Human Cytokine ELISA plates manufactured by Signosis, Inc.Adiponectin and ICACM-1 where elevated in all patients pre and post treatment. Cytokines found to be increased in patients treated with RSO-021 included IL-1B, IL-8, and Resistin. Cytokines found to be decreased following treatment included IL-13, IL-31, and IP-10. Together, these data provide the first evidence for the molecular activity of TS in patients and the resulting changes to cytokine profiles. The downstream effects of these changes to cytokine levels on cellular composition and patient responses is an ongoing focus of our research teams.

Citation Format: Terri Messier, Molly Scotland, George Naumov, Sean Dulloo, Dean Fennell, Brian Cunniff. Effects of RSO-021 on cytokine profiles of malignant pleural effusions from patients enrolled in the MITOPE phase 1/2 clinical trial [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B022.
Abstract B027: Synergy between ONC201 and temozolomide on ATF4 integrated stress response in glioblastoma
Authors: Chen Josephine , George Andrew , Zhou Lanlan , El-Deiry Wafik
Published: December 2023

Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults with a median survival time of 15 months. The standard of care involves surgical resection followed by chemoradiotherapy. Even with the full course of treatment, GBM is uncurable, and patients eventually relapse. Although temozolomide (TMZ) is the first-choice chemotherapeutic for GBM, tumor drug resistance limits the effects of the treatment. There is a growing need for new therapies with enhanced efficacy on GBM tumors. ONC201 is a TNF-related apoptosis-inducing ligand (TRAIL)-inducing compound that is increasingly being studied for GBM treatment. This small molecule induces apoptosis by activating the integrated stress response, which involves transcription factors ATF4 and CHOP. Subsequently, these transcription factors upregulate proapoptotic protein TRAIL and its receptor, Death Receptor 5 (DR5).   This study aims to investigate the combinatory effects of chemotherapeutics ONC201 and TMZ on GBM. Preliminary studies examined the cell viability of GBM cell line U251MG using ONC201 concentrations up to 40uM and TMZ concentrations up to 200uM. Additionally, western blots performed with 0, 2, and 4uM of ONC201 in combination with 0 and 120uM of TMZ demonstrated greater ATF4 expression when both drugs were administered concurrently than when either drug was administered alone. Subsequent western blots were conducted using three GBM cell lines (U251MG, T98G, and SNB19-GFP) at three time points (8, 24, and 48 hours). All cell lines were treated with 0 and 4uM of ONC201 in combination with 0 and 120uM of TMZ. At all three time points and for all three cell lines, ATF4 expression increased in the combined presence of TMZ and ONC201. However, the effects of TMZ on ONC201-induced ATF4 expression were most pronounced in U251MG. These observations suggest synergy between chemotherapeutics ONC201 and TMZ in the ATF4 integrated stress response pathway in GBM. By exploring the effects of this dual treatment on upstream and downstream factors in the integrated stress response pathway, we can identify, characterize, and potentially target the root cause of this synergy.

Citation Format: Josephine Chen, Andrew George, Lanlan Zhou, Wafik El-Deiry. Synergy between ONC201 and temozolomide on ATF4 integrated stress response in glioblastoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B027.
Abstract B028: Phosphodiesterase 3A modulators sensitize tumor cells to Bcl-2/Bcl-xL inhibitors
Authors: Toivanen Kirsi L. J. , Murumägi Astrid , Arjama Mariliina A. , Merikoski Nanna J. , Salmikangas Sami I. , Kallioniemi Olli P. , Böhling Tom O. , Sihto Harri J.
Published: December 2023

Phosphodiesterase 3A (PDE3A) modulators are promising anticancer agents for tumors that coexpress PDE3A and Schlafen 12 (SLFN12), including sarcomas. The cytotoxic effect of these modulators is based on their ability to form a complex between PDE3A and SLFN12, and correlates with the expression levels of the two proteins. In cases where the two proteins are only moderately expressed, PDE3A modulator efficacy may remain poor and additional therapeutic options are needed. In this study, we investigated the combinatorial effects of a PDE3A modulator, anagrelide, with 526 other oncological compounds in two PDE3A and SLFN12 expressing liposarcoma cell lines (SA4 and GOT3). Both cell lines were responsive to PDE3A modulators, as expected. Interestingly, we found synergy with seven different drug classes that can be grouped based on their protein and protein family targets: Bcl-2l/Bcl-xL, HDAC, integrin α2 (ITGA2), mTOR, NEDD-activating enzyme E1 regulatory subunit proteins, and PAK. Additional detailed drug combination synergy studies in PDE3A modulator –sensitive liposarcoma, gastrointestinal stromal tumor, melanoma, and astrocytoma cell lines indicated a sensitizing effect of PDE3A modulators to Bcl-2/Bcl-xL inhibitors. These cell lines, excluding GOT3, showed no response to Bcl-2/Bcl-xL inhibitors otherwise. Furthermore, we discovered that the sensitization effect depends on the coexpression of PDE3A and SLFN12, and that cotreatment resulted in stronger activation of programmed cell death. Our findings suggest additional combinatorial opportunities between PDE3A modulators and inhibitors of key cancer pathways that could be explored for their therapeutic value.

Citation Format: Kirsi L. J. Toivanen, Astrid Murumägi, Mariliina A. Arjama, Nanna J. Merikoski, Sami I. Salmikangas, Olli P. Kallioniemi, Tom O. Böhling, Harri J. Sihto. Phosphodiesterase 3A modulators sensitize tumor cells to Bcl-2/Bcl-xL inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B028.
Abstract B090: Partially open conformation of the G323E mutated HIF-2α PASB domain captured by X-ray crystallography
Authors: Shia Steven , Malgapo Ian , Chen Jeffrey , Pham Amber , Meleza Cesar A , Shen Lunda , Morar Mariya , Lawson Kenneth V , Gauthier Kelsey E Sivick , Kwon Hyock J
Published: December 2023

Under hypoxic conditions, vital cell processes such as angiogenesis, erythropoiesis, cell proliferation and metabolism are regulated by a group of transcription factors known as hypoxia-inducible factors (HIFs).  These proteins belong to the helix-loop-helix family of transcription factors and require heterodimerization to function. Constitutively expressed HIF-1β protein forms a heterodimer with one of the oxygen-labile counterparts: HIF-1α, HIF-2α, or HIF-3α.  The HIF-αs are degraded under normoxic conditions via ubiquitination by the von Hippel Lindau (VHL) E3 ubiquitin ligase and become available for dimerization under either hypoxia or VHL dysfunction.  Certain cancer types take advantage of this HIF-regulated transcription for survival and growth, as exemplified by VHL-deficient clear cell renal cell carcinoma (ccRCC).  Inhibitors aimed at disruption of the HIF-1β:HIF-2α heterodimer have been advanced into clinical development, including belzutifan (approved by the Food and Drug Administration for adult patients with VHL disease who require therapy for RCC among other indications) and AB521 (Arcus Biosciences). This class of small molecules functions by binding to and causing a conformational change in the internal cavity of the PasB domain of HIF-2α.  A mutation within this internal cavity, G323E, was  reported in a patient undergoing treatment with HIF-2α inhibitor. This mutation restored the ability of HIF-1β to heterodimerize with HIF-2α in presence of the inhibitor.  To better understand this potential resistance mechanism and how the G323E mutation affects inhibitor binding, we used X-ray crystallography to examine the structure of the mutant HIF-2α PasB domain in complex with a novel small molecule inhibitor active in vitro against the G323E mutant form.  We report a co-crystal structure that reveals a partially disordered open conformation of the HIF-2α PasB domain. This structure strengthens existing hypotheses regarding the route of compound entry into the HIF-2α PasB cavity and lays the foundation for structure-based design of HIF-2α PasB G323E-active inhibitors.

Citation Format: Steven Shia, Ian Malgapo, Jeffrey Chen, Amber Pham, Cesar A Meleza, Lunda Shen, Mariya Morar, Kenneth V Lawson, Kelsey E Sivick Gauthier, Hyock J Kwon. Partially open conformation of the G323E mutated HIF-2α PASB domain captured by X-ray crystallography [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B090.
Abstract B103: Statins decrease mesothelial clearance, an early step in ovarian cancer metastasis
Authors: Reilly Brendan M , Martin Olivia R , Mackey Allison F , Walker Sarah R
Published: December 2023

Ovarian cancer has a low 5-year survival rate often associated with detection of late-stage cancer due to the difficulty of early detection. Ovarian cancer metastasis can occur via a distinct mechanism compared to other solid cancers. Ovarian cancer spheroids slough off from the primary tumor. In the ascites, these spheroids attach to and clear the protective layer of mesothelial cells that line the peritoneum. Once this mesothelial clearance occurs, the ovarian spheroids can invade the connective tissue and metastasize to further parts of the body or grow implanted in the peritoneum. Targeting mesothelial clearance may be a new mechanism to treat ovarian cancer. Previously, it was shown that the use of statins, drugs commonly used to control cholesterol, is associated with decreased ovarian cancer occurrence. In addition, statins have the potential to interfere with several signaling pathways that are known to play key roles in cancer including metastasis. The potential for statins to target metastasis could be beneficial in treating cancers like ovarian cancer that tend to be found in metastatic stages. Therefore, we hypothesized that statins would reduce mesothelial clearance by ovarian cancer spheroids. Using an in vitro mesothelial clearance assay, we have found that statins, such as simvastatin and lovastatin, decrease the mesothelial clearing abilities of ovarian cancer spheroids. To better understand the mechanism of mesothelial clearance inhibition, we analyzed several known downstream pathways. Targeting HMGCR by siRNA, the known molecular target of statins, reduced mesothelial clearance. In addition, targeting Rac1 and CDC42 using the inhibitor AZA1 has a similar inhibitory effect as simvastatin on mesothelial clearance. This suggests that inhibition of Rac1 by statins may be the mechanism that statins inhibit mesothelial clearance. To support this, siRNA knockdown of RAC1 suggests the importance of Rac1 for mesothelial clearance. Previously, we found that treatment of ovarian spheroids with geranylgeranyl-pyrophosphate partially rescued the inhibition of viability by statins. Therefore, our current working hypothesis is that statins disrupt the function of Rac1 by reducing the cellular supply of geranylgeranyl-pyrophosphate through inhibiting HMGCR and the mevalonate pathway. While we are currently further analyzing the mechanisms behind this pathway, we believe this evidence suggests an exciting new therapeutic route for treating ovarian cancer.

Citation Format: Brendan M Reilly, Olivia R Martin, Allison F Mackey, Sarah R Walker. Statins decrease mesothelial clearance, an early step in ovarian cancer metastasis [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B103.