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2022 ◽  
Vol 23 (2) ◽  
pp. 820
Author(s):  
Davide Ciardiello ◽  
Brigida Anna Maiorano ◽  
Paola Parente ◽  
Maria Grazia Rodriquenz ◽  
Tiziana Pia Latiano ◽  
...  

Biliary tract cancers (BTC) represent a heterogeneous and aggressive group of tumors with dismal prognosis. For a long time, BTC has been considered an orphan disease with very limited therapeutic options. In recent years a better understanding of the complex molecular landscape of biology is rapidly changing the therapeutic armamentarium. However, while 40–50% of patients there are molecular drivers susceptible to target therapy, for the remaining population new therapeutic options represent an unsatisfied clinical need. The role of immunotherapy in the continuum of treatment of patients with BTC is still debated. Despite initial signs of antitumor-activity, single-agent immune checkpoint inhibitors (ICIs) demonstrated limited efficacy in an unselected population. Therefore, identifying the best partner to combine ICIs and predictive biomarkers represents a key challenge to optimize the efficacy of immunotherapy. This review provides a critical analysis of completed trials, with an eye on future perspectives and possible biomarkers of response.


2022 ◽  
Vol 11 ◽  
Author(s):  
Justin Watts ◽  
Tara L. Lin ◽  
Alice Mims ◽  
Prapti Patel ◽  
Cynthia Lee ◽  
...  

APVO436 is a recombinant bispecific antibody designed to direct host cytotoxic T-cells to CD123-expressing blast cells in patients with hematologic malignancies. APVO436 showed promising tolerability and single-agent activity in relapsed or refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The primary purpose of this post-hoc analysis was to evaluate the therapeutic and pharmacodynamic effects of APVO436 in 14 R/R AML/MDS patients who had failed treatment with hypomethylating agents (HMA) or venetoclax plus HMA prior to being enrolled in the APVO436 Phase 1 dose-escalation study that was recently completed. Eight of these 14 patients had R/R AML and had failed treatment with HMA (N=2) or venetoclax plus HMA (N=6). The remaining 6 patients had R/R MDS and had also failed treatment with HMA (N=5) or venetoclax plus HMA (N=1). They were treated with APVO436 at submicrogram dose levels >0.08 mcg/kg that were active in preclinical NOD/SCID mouse xenograft models of AML. APVO436 activated patients’ T-cells as evidenced by reduced numbers of circulating CD123+CD34+ and CD33+CD34+ peripheral blasts. Single-agent activity was observed at dose levels ranging from 0.1 mcg/kg to 0.7 mcg/kg in 4 R/R AML patients (50%), including 3 patients with prolonged stable disease (SD) and one patient with complete remission (CR). Likewise, 3 MDS patients had SD (50%) and 3 additional MDS patients (50%) had a marrow CR at dose levels ranging from 0.1 mcg/kg to 0.8 mcg/kg. The median survival for the combined group of 14 R/R AML/MDS patients was 282 days. This early evidence of single-agent activity of APVO436 in R/R AML/MDS patients who failed HMA with or without venetoclax provides proof of concept supporting its in vivo immunomodulatory and anti-leukemic activity and warrants further investigation of its clinical impact potential.


2022 ◽  
Author(s):  
Sandra Misale ◽  
Rona Yaeger ◽  
Riccardo Mezzadra ◽  
Jenna Sinopoli ◽  
Yu Bian ◽  
...  

Abstract KRAS G12C inhibitors, such as sotorasib, have rapidly moved through clinical development and are poised to transform care of patients with KRAS G12C mutant cancers, in particular non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). Clinical efficacy is achieved in NSCLC as a single agent and in CRC in combination with anti-EGFR monoclonal antibodies, however, secondary resistance impairs the effects of KRAS G12C blockade. In this work, we sought to determine the mechanisms of acquired resistance to concomitant KRAS-EGFR inhibition. In cell lines, patient-derived xenograft, and patient samples, a heterogeneous pattern of putative resistance alterations expected primarily to prevent inhibition of ERK signalling by drug can be detected at progression. Serial analysis of patient blood samples on treatment demonstrates that most of these alterations are detected at a low frequency that does not increase substantially and sometimes disappears over time, with the exception of KRAS G12C amplification which rises in step with tumour marker levels and clinical progression. Here we show that a CRC cell line that acquired resistance to sotorasib-cetuximab combination through KRAS G12C amplification became addicted to these agents and undergoes oncogene-induced senescence upon drug withdrawal. Accordingly, the KRAS G12C signal in circulating DNA from relapsed patients harbouring G12C amplification rapidly recedes upon treatment holiday. These data indicate that KRAS G12C amplification is a recurrent resistance mechanism to KRAS-EGFR co-inhibition and suggest a potential therapeutic vulnerability, whereby therapies that target this senescence response at drug withdrawal may overcome resistance to KRAS G12C-EGFR inhibition.


Biomedicines ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 149
Author(s):  
David J. Wooten ◽  
Indu Sinha ◽  
Raghu Sinha

Survival rate for pancreatic cancer remains poor and newer treatments are urgently required. Selenium, an essential trace element, offers protection against several cancer types and has not been explored much against pancreatic cancer specifically in combination with known chemotherapeutic agents. The present study was designed to investigate selenium and Gemcitabine at varying doses alone and in combination in established pancreatic cancer cell lines growing in 2D as well as 3D platforms. Comparison of multi-dimensional synergy of combinations’ (MuSyc) model and highest single agent (HSA) model provided quantitative insights into how much better the combination performed than either compound tested alone in a 2D versus 3D growth of pancreatic cancer cell lines. The outcomes of the study further showed promise in combining selenium and Gemcitabine when evaluated for apoptosis, proliferation, and ENT1 protein expression, specifically in BxPC-3 pancreatic cancer cells in vitro.


2022 ◽  
Vol 11 ◽  
Author(s):  
Amanda B. Kagan ◽  
Blake S. Moses ◽  
Bryan T. Mott ◽  
Ganesha Rai ◽  
Nicole M. Anders ◽  
...  

Acute myeloid leukemia (AML) remains a devastating disease, with low cure rates despite intensive standard chemotherapy regimens. In the past decade, targeted antileukemic drugs have emerged from research efforts. Nevertheless, targeted therapies are often effective for only a subset of patients whose leukemias harbor a distinct mutational or gene expression profile and provide only transient antileukemic responses as monotherapies. We previously presented single agent and combination preclinical data for a novel 3-carbon-linked artemisinin-derived dimer (3C-ART), diphenylphosphate analog 838 (ART838), that indicates a promising approach to treat AML, given its demonstrated synergy with targeted antileukemic drugs and large therapeutic window. We now report new data from our initial evaluation of a structurally distinct class of 2-carbon-linked dimeric artemisinin-derived analogs (2C-ARTs) with prior documented in vivo antimalarial activity. These 2C-ARTs have antileukemic activity at low (nM) concentrations, have similar cooperativity with other antineoplastic drugs and comparable physicochemical properties to ART838, and provide a viable path to clinical development.


2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Keivan Mojtahedi ◽  
Kimia Kiani ◽  
Marco Santello ◽  
Qiushi Fu

AbstractThe extent to which hand dominance may influence how each agent contributes to inter-personal coordination remains unknown. In the present study, right-handed human participants performed object balancing tasks either in dyadic conditions with each agent using one hand (left or right), or in bimanual conditions where each agent performed the task individually with both hands. We found that object load was shared between two hands more asymmetrically in dyadic than single-agent conditions. However, hand dominance did not influence how two hands shared the object load. In contrast, hand dominance was a major factor in modulating hand vertical movement speed. Furthermore, the magnitude of internal force produced by two hands against each other correlated with the synchrony between the two hands’ movement in dyads. This finding supports the important role of internal force in haptic communication. Importantly, both internal force and movement synchrony were affected by hand dominance of the paired participants. Overall, these results demonstrate, for the first time, that pairing of one dominant and one non-dominant hand may promote asymmetrical roles within a dyad during joint physical interactions. This appears to enable the agent using the dominant hand to actively maintain effective haptic communication and task performance.


Author(s):  
Anju Anna Abraham ◽  
Anoop T.M ◽  
Rona Joseph P. ◽  
Arun Vasudevan ◽  
Bhavya S. Kumar

Abstract Background Neoplastic meningitis (NM) is considered as a terminal event with poor prognosis. Its impact in clinical oncology is growing. Objective To analyze the clinical outcome of patients with carcinoma breast diagnosed with NM. Materials and Methods This study was an observational study in breast cancer patients diagnosed with NM. Patients with typical clinical symptoms and signs with either presence of cerebrospinal fluid (CSF) cytology positive for neoplastic cells or typical radiological features of leptomeningeal involvement in the presence of neurological symptoms or signs were taken as leptomeningeal metastasis (LM) or NM. The estimation of survival was done by Kaplan–Meier method. Results Out of 1,200 patients diagnosed with carcinoma breast during the study period, 15 developed NM. The median age of study population was 51 (range: 44–55) years. Most common presentations were headache (47%), vomiting (47%), diplopia (20%), seizure (20%), and cerebellar signs (7%). Seven (46%) patients were hormone receptor positive, four (30%) were HER2 (Human epidermal growth factor receptor 2) positive and seven (46%) were triple-negative breast cancer. Median time to develop LM from the time of diagnosis of breast cancer was 6 (range: 3–8) months. Nine patients (90%) had features of NM in CSF cytology. Thirteen patients received palliative whole brain radiotherapy (20 Gy in five fractions). Nine out of 12 patients received single-agent Capecitabine as first-line chemotherapy after palliative radiation therapy (RT). Intrathecal methotrexate was given for seven patients. The median overall survival was 3 (range: 0.5–4) months. Conclusion LM is a very aggressive metastatic disease with poor outcome. There is an unmet need for proper guidelines and an overwhelming necessity for a better focus on research for new modalities of disease in this scenario.


Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 316
Author(s):  
Chih-Hsi Scott Kuo ◽  
Tzu-Hsuan Chiu ◽  
Pi-Hung Tung ◽  
Chi-Hsien Huang ◽  
Jia-Shiuan Ju ◽  
...  

Background: Treatment outcome between afatinib alone or with bevacizumab in non-small cell lung cancer (NSCLC) patient with epidermal growth factor receptor (EGFR) mutation remains insufficiently reported. Methods: A total of 405 advanced NSCLC patients with sensitizing-EGFR mutation receiving first-line single-agent afatinib or with bevacizumab were grouped and propensity score-matched. Progression-free survival (PFS), overall survival (OS) and secondary T790M mutation were analyzed. Results: In the original cohort, 367 (90.6%) patients received afatinib treatment alone and 38 (9.4%) patients received afatinib plus bevacizumab. Patients who received bevacizumab combination were significantly younger (54.6 ± 10.9 vs. 63.9 ± 11.5; p < 0.001) compared to the afatinib alone group. After propensity score matching, the afatinib alone and afatinib plus bevacizumab groups contained 118 and 34 patients, respectively. A non-significantly higher objective response was noted in the afatinib plus bevacizumab group (82.4% vs. 67.8%; p = 0.133). In the propensity score-matched cohort, a bevacizumab add-on offered no increased PFS (16.1 vs. 15.0 months; p = 0.500), risk reduction of progression (HR 0.85 [95% CI, 0.52–1.40]; p = 0.528), OS benefit (32.1 vs. 42.0 months; p = 0.700), nor risk reduction of death (HR 0.85 [95% CI, 0.42–1.74] p = 0.660) compared to the single-agent afatinib. The secondary T790M rate in afatinib plus bevacizumab and afatinib alone groups was similar (56.3% vs. 49.4%, p = 0.794). Multivariate analysis demonstrated that EGFR L858R (OR 0.51 [95% CI, 0.26–0.97]; p = 0.044), EGFR uncommon mutation (OR 0.14 [95% CI, 0.02–0.64]; p = 0.021), and PFS longer than 12 months (OR 2.71 [95% CI, 1.39–5.41]; p = 0.004) were independent predictors of secondary T790M positivity. Conclusion: Bevacizumab treatment showed moderate efficacy in real-world, afatinib-treated NSCLC patients with EGFR-sensitizing mutation.


Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 289
Author(s):  
Giovanni Luca Gravina ◽  
Alessandro Colapietro ◽  
Andrea Mancini ◽  
Alessandra Rossetti ◽  
Stefano Martellucci ◽  
...  

Cell proliferation requires the orchestrated actions of a myriad of proteins regulating DNA replication, DNA repair and damage tolerance, and cell cycle. Proliferating cell nuclear antigen (PCNA) is a master regulator which interacts with multiple proteins functioning in these processes, and this makes PCNA an attractive target in anticancer therapies. Here, we show that a cell-penetrating peptide containing the AlkB homolog 2 PCNA-interacting motif (APIM), ATX-101, has antitumor activity in a panel of human glioblastoma multiforme (GBM) cell lines and patient-derived glioma-initiating cells (GICs). Their sensitivity to ATX-101 was not related to cellular levels of PCNA, or p53, PTEN, or MGMT status. However, ATX-101 reduced Akt/mTOR and DNA-PKcs signaling, and a correlation between high Akt activation and sensitivity for ATX-101 was found. ATX-101 increased the levels of γH2AX, DNA fragmentation, and apoptosis when combined with radiotherapy (RT). In line with the in vitro results, ATX-101 strongly reduced tumor growth in two subcutaneous xenografts and two orthotopic GBM models, both as a single agent and in combination with RT. The ability of ATX-101 to sensitize cells to RT is promising for further development of this compound for use in GBM.


Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 282
Author(s):  
W. Quinn O’Neill ◽  
Xiujie Xie ◽  
Shanying Gui ◽  
Heping Yu ◽  
Jacqueline Davenport ◽  
...  

Human papillomavirus-associated head and neck squamous cell carcinoma (HPV+ HNSCC) is recognized as a distinct disease with unique etiology and clinical features. Current standard of care therapeutic modalities are identical for HPV+ and HPV− HNSCC and thus, there remains an opportunity to develop innovative pharmacologic approaches to exploit the inherent vulnerabilities of HPV+ HNSCC. In this study, using an inducible HPVE6E7 knockdown system, we found that HPV+ HNSCC cells are addicted to HPVE6E7, such that loss of these viral oncogenes impaired tumorigenicity in vitro and in vivo. A number of druggable pathways, including PPAR and Wnt, were modulated in response to HPVE6E7 loss. Fenofibrate showed significant anti-proliferative effects in a panel of HPV+ cancer cell lines. Additionally, fenofibrate impaired tumor growth as monotherapy and potentiated the activity of cisplatin in a pre-clinical HPV+ animal model. Systemic fenofibrate treatment induced p53 protein accumulation, and surprisingly, re-programmed the tumor-immune microenvironment to drive immune cell infiltration. Since fenofibrate is FDA-approved with a favorable long-term safety record, repositioning of this drug, as a single agent or in combination with cisplatin or checkpoint blockade, for the HPV+ HNSCC setting should be prioritized.


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