Combo Beat Single Agent for Boosting BMD

The lead compound, an ⍺-N-heterocyclic carboxaldehyde thiosemicarbazone HCT-13, was highly potent against a panel of pancreatic, small cell lung carcinoma, and prostate cancer models, with IC90 values in the low-to-mid nanomolar range. We show that the cytotoxicity of HCT-13 is copper-dependent, that it acts as a copper ionophore, induces production of reactive oxygen species (ROS), and promotes mitochondrial dysfunction and S-phase arrest. Lastly, DNA damage response/replication stress response (DDR/RSR) pathways, specifically Ataxia-Telangiectasia Mutated (ATM) and Rad3-related protein kinase (ATR), were identified as actionable adaptive resistance mechanisms following HCT-13 treatment. Taken together, HCT-13 is potent against solid tumor models and warrants in vivo evaluation against aggressive tumor models, either as a single agent or as part of a combination therapy.

Download Full-text

Copanlisib Has Activity As a Single Agent and in Combination with Carfilzomib and Response Correlates with Phospho-S6 Level

Clinical Lymphoma Myeloma & Leukemia ◽

10.1016/j.clml.2017.03.238 ◽

2017 ◽

Vol 17 (1) ◽

pp. e132

Author(s):

Sarah Larson ◽

Mao Yu Peng ◽

Andrae Vandross ◽

Monica Mead ◽

Erika Von Euw ◽

...

Keyword(s):

Single Agent

Download Full-text

A Population-Based Retrospective Study of Biliary Tract Cancers in Alberta, Canada

Current Oncology ◽

10.3390/curroncol28010044 ◽

2021 ◽

Vol 28 (1) ◽

pp. 417-427

Author(s):

Carissa Beaulieu ◽

Arthur Lui ◽

Dimas Yusuf ◽

Zainab Abdelaziz ◽

Brock Randolph ◽

...

Keyword(s):

Biliary Tract ◽

Demographic Data ◽

Performance Status ◽

Single Agent ◽

Eastern Cooperative Oncology Group ◽

Intrahepatic Bile Duct ◽

Population Based ◽

Phase Iii ◽

First Line ◽

Biliary Tract Cancers

Background: Biliary tract cancers (BTC) are uncommon malignancies and are underrepresented in the literature. Methods: We performed a retrospective population-based review of adult patients with biopsy-confirmed BTC in Alberta from 2000 to 2015. Demographic data, risk factors, symptoms, treatment, and staging data were collected and analyzed. Survival analyses were completed. Results: A total of 1604 patients were included in our study, of which 766 (47.8%) were male. The median age at diagnosis was 68 (range 19–99). There were 374 (23.3%) patients with resectable tumors at diagnosis versus 597 (37.2%) with unresectable tumors. Of the patients, 380 (21.5%) received chemotherapy (CT) and 81 (5.0%) underwent radiation therapy. There was a clear trend with worsening stage and performance status associated with shorter median overall survival (OS). Ampulla of Vater tumors had the best median OS (25.69 months), while intrahepatic bile duct cancers had the worst (5.78 months). First-line palliative CT regimens included gemcitabine+cisplatin (OS 14.98 months (mo), n = 212), single agent gemcitabine (OS 12.42 mo, n = 22), capecitabine (OS 8.12 mo, n = 8), and capecitabine+gemcitabine (OS 6.93 mo, n = 13). Patients with advanced or metastatic disease who received first-line gemcitabine+cisplatin had a median OS of 11.8 months (n = 119). Conclusion: BTCs have poor survival. Worse outcomes occur in higher stage and poorer Eastern Cooperative Oncology Group (ECOG) performance status patients across all tumor subtypes. Tumor resectability at diagnosis was associated with better OS. Our study supports the use of gemcitabine+cisplatin as a combination first-line palliative CT, as patients treated in Alberta have a comparable OS to that reported in the ABC-02 phase III study.

Download Full-text

DDRE-06. CELLULAR STRESS RESPONSE IN DIPG THERAPY

Neuro-Oncology ◽

10.1093/neuonc/noaa215.251 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii62-ii62

Author(s):

Sreepradha Sridharan ◽

Arif Harmanci ◽

Robert Siddaway ◽

Tara Dobson ◽

Jyothishmathi Swaminathan ◽

...

Keyword(s):

Stress Response ◽

Single Cell ◽

Synthetic Lethality ◽

Clonal Evolution ◽

Single Agent ◽

Objective Response ◽

Hdac Inhibitors ◽

Pediatric Brain Tumor ◽

Dominant Negative ◽

Cellular Stress Response

Abstract Diffuse Intrinsic Pontine Glioma (DIPG) is an incurable pediatric brain tumor of the pons and brainstem. Therefore, there is a desperate need for new therapeutics. Genomic profiling of tumors identified a highly prevalent dominant negative somatic mutation at lysine (K)-27 in histone genes HIST1H3B and H3F3A. Clonal evolution modeling suggests these mutations are truncal, and studies have demonstrated their contribution to tumorigenesis. ONC201, a first-in-class DRD2 antagonist and ClpP agonist is an anticancer drug developed by Oncoceutics, which targets the unfolded protein response (UPR) and integrated stress response (ISR) signaling and is actively being investigated in patients with recurrent H3 K27M-mutant gliomas. In adults with recurrent glioma, single agent studies showed benign-safety, no dose-limiting toxicities and a durable objective response when administered orally. In addition, intra-tumoral drug levels exceeded therapeutic thresholds, and induced tumor cell apoptosis. Based on this and response seen in a pediatric patient with DIPG for whom compassionate use of ONC201 was approved, a multi-arm, non-randomized multi-institutional Phase I clinical trial (NCT03416530) is actively accruing patients. However, the strength of UPR and ISR in DIPGs and their effect on DIPG response to ONC201 is not known. Our group employed bulk/single cell transcriptomic and single cell proteomic approaches to demonstrate substantial heterogeneity in UPR and ISR signaling in human DIPG samples. Consistent with this, DIPG cell lines exhibited considerable variability in sensitivity to ONC201. Single cell profiling identified tumor sub-populations with significant proliferative capacity even after ONC201 exposure. Incomplete response promotes recurrence. To target these cells, we performed a synthetic lethality screen with a library of 360 FDA-approved CNS penetrant compounds, which identified HDAC inhibitors and DNA damage-inducing chemotherapy as having synergy with ONC201. Thus, we suggest that tumor heterogeneity impacts sensitivity to ONC201 and that this can be reduced by combination treatments.

Download Full-text

Characteristics and Treatment Challenges of Non-Clear Cell Renal Cell Carcinoma

Cancers ◽

10.3390/cancers13153807 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3807

Author(s):

Pierangela Sepe ◽

Arianna Ottini ◽

Chiara Carlotta Pircher ◽

Andrea Franza ◽

Melanie Claps ◽

...

Keyword(s):

Renal Cell ◽

Kinase Inhibitors ◽

Clear Cell ◽

Case Reports ◽

Treatment Options ◽

Single Agent ◽

Growth Factor Receptor ◽

Mtor Inhibitors ◽

Cell Renal Cell Carcinoma ◽

Clear Cell Rcc

Non-clear cell renal cell carcinomas (RCC) comprise several rare and poorly described diseases, often characterized by bad prognosis and with no standard treatments available. The gap in their clinical management is linked to the poor molecular characterization in handling the treatment of non clear-cell RCC with untailored therapies. Due to their rarity, non-clear RCC are in fact under-represented in prospective randomized trials. Thus, treatment choices are based on extrapolating results from clear cell RCC trials, retrospective data, or case reports. Over the last two decades, various options have been considered as the mainstay for the treatment of metastatic RCC (mRCC), including angiogenesis inhibitors, vascular endothelial growth factor receptor inhibitors, other tyrosine kinase inhibitors (TKIs), as well as MET inhibitors and mammalian targeting of rapamycin (mTOR) inhibitors. More recently, the therapeutic armamentarium has been enriched with immunotherapy, alone or in combination with targeted agents that have been shown to significantly improve outcomes of mRCC patients, if compared to TKI single-agent. It has been widely proven that non-clear cell RCC is a morphologically and clinically distinct entity from its clear cell counterpart but more knowledge about its biology is certainly needed. Histology-specific collaborative trials are in fact now emerging to investigate different treatments for non-clear cell RCC. This review summarizes pathogenetic mechanisms of non-clear cell RCC, the evolution of treatment paradigms over the last few decades, with a focus on immunotherapy-based trials, and future potential treatment options.

Download Full-text

Cancer-associated fibroblast secretion of PDGFC promotes gastrointestinal stromal tumor growth and metastasis

Oncogene ◽

10.1038/s41388-021-01685-w ◽

2021 ◽

Vol 40 (11) ◽

pp. 1957-1973

Author(s):

Hyunho Yoon ◽

Chih-Min Tang ◽

Sudeep Banerjee ◽

Mayra Yebra ◽

Sangkyu Noh ◽

...

Keyword(s):

Signal Transduction ◽

Tumor Growth ◽

Gastrointestinal Stromal Tumor ◽

Single Agent ◽

Stromal Tumor ◽

Paracrine Signaling ◽

Mesenchymal Transition ◽

Tumor Growth And Metastasis ◽

Factor C

AbstractTargeted therapies for gastrointestinal stromal tumor (GIST) are modestly effective, but GIST cannot be cured with single agent tyrosine kinase inhibitors. In this study, we sought to identify new therapeutic targets in GIST by investigating the tumor microenvironment. Here, we identified a paracrine signaling network by which cancer-associated fibroblasts (CAFs) drive GIST growth and metastasis. Specifically, CAFs isolated from human tumors were found to produce high levels of platelet-derived growth factor C (PDGFC), which activated PDGFC-PDGFRA signal transduction in GIST cells that regulated the expression of SLUG, an epithelial-mesenchymal transition (EMT) transcription factor and downstream target of PDGFRA signaling. Together, this paracrine induce signal transduction cascade promoted tumor growth and metastasis in vivo. Moreover, in metastatic GIST patients, SLUG expression positively correlated with tumor size and mitotic index. Given that CAF paracrine signaling modulated GIST biology, we directly targeted CAFs with a dual PI3K/mTOR inhibitor, which synergized with imatinib to increase tumor cell killing and in vivo disease response. Taken together, we identified a previously unappreciated cellular target for GIST therapy in order to improve disease control and cure rates.

Download Full-text

353 Safety and efficacy of tumor infiltrating lymphocytes (TIL, LN-145) in combination with pembrolizumab for advanced, recurrent or metastatic HNSCC

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0353 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A378-A378

Author(s):

Antonio Jimeno ◽

Sophie Papa ◽

Missak Haigentz ◽

Juan Rodríguez-Moreno ◽

Julian Schardt ◽

...

Keyword(s):

Cell Therapy ◽

Checkpoint Inhibitors ◽

Adoptive Cell Therapy ◽

Single Agent ◽

Objective Response ◽

Tumor Resection ◽

Tumor Infiltrating Lymphocytes ◽

Open Label ◽

Safety And Efficacy ◽

Infiltrating Lymphocytes

BackgroundSingle agent checkpoint inhibitors (CPI) are an approved first or second-line therapy in head and neck squamous cell carcinoma (HNSCC), but their efficacy is limited. Adoptive cell therapy with tumor infiltrating lymphocytes (TIL, LN-145) has demonstrated efficacy in multiple malignancies alone or in combination with CPI. To improve HNSCC therapy, a combination of pembrolizumab and LN-145 was explored.MethodsIOV-COM-202 is an ongoing Phase 2 multicenter, multi-cohort, open-label study evaluating LN-145 in multiple settings and indications, and here we report cohort 2A which enrolled CPI naïve HNSCC patients who received the combination of LN-145 and pembrolizumab. Key eligibility criteria include up to 3 lines of prior therapy, ECOG <1, at least one resectable metastasis for LN-145 production, and at least another measurable lesion after tumor resection. Primary endpoints are ORR per RECIST v1.1 by investigator and safety as measured by the incidence of grade ≥ 3 treatment-emergent adverse events (TEAEs). LN-145 production method uses central GMP manufacturing in a 22-day process yielding a cryopreserved TIL product (figure 1). Preconditioning chemotherapy consists of cyclophosphamide/fludarabine, followed by LN-145, and then < 6 doses of IL-2 over <3 days. Pembrolizumab is initiated post-tumor harvest but prior to LN-145 and continues after LN-145 infusion Q3W until toxicity or progression (figure 2).ResultsNine (N=9) HNSCC patients have received LN-145 plus pembrolizumab, with a median duration of follow up of 6.9 months. Nine and 8 patients were evaluable for safety and efficacy, respectively. Mean number of prior therapies was 1.1 with 89% of the patients having received prior chemotherapy. Four were HPV+, 2 HPV-, 3 unknown. The Treatment Emergent Adverse Event (TEAE) profile was consistent with the underlying advanced disease and the known AE profiles of pembrolizumab, the lymphodepletion and IL-2 regimens. The most common TEAE were chills, hypotension, anemia, thrombocytopenia, pyrexia, fatigue and tachycardia. Four patients had a confirmed, objective response with an ORR of 44% (1 CR, 3 PR, 4 SD, 1 NE) per RECIST 1.1. The disease control rate at data cutoff was 89% in 9 patients, and 7 of the 8 evaluable patients (87.5%) had a reduction in target lesions. Median DOR was not reached.Abstract 353 Figure 1Iovance LN-145 (autologous TIL cell therapy product) ManufacturingAbstract 353 Figure 2IOV-COM-202 Study SchemaConclusionsLN-145 can be safely combined with pembrolizumab in patients with metastatic HNSCC. LN-145 plus pembrolizumab shows early signs of improved efficacy particularly when compared with literature reports of pembrolizumab alone in a comparable patient population. Enrollment is ongoing and updated data will be presented.Trial RegistrationNCT03645928Ethics ApprovalThe study was approved by Advarra Institutional Review Board, under protocol number: Pro00035064.

Download Full-text

Platform study of genotyping-guided precision medicine for rare solid tumours: a study protocol for a phase II, non-randomised, 18-month, open-label, multiarm, single-centre clinical trial testing the safety and efficacy of multiple Chinese-approved targeted drugs and PD-1 inhibitors in the treatment of metastatic rare tumours

BMJ Open ◽

10.1136/bmjopen-2020-044543 ◽

2021 ◽

Vol 11 (6) ◽

pp. e044543

Author(s):

Shuhang Wang ◽

Hui-Yao Huang ◽

Dawei Wu ◽

Hong Fang ◽

Jianming Ying ◽

...

Keyword(s):

Clinical Trial ◽

Targeted Therapy ◽

Single Agent ◽

Solid Tumours ◽

Targeted Drugs ◽

Gene Fusions ◽

Single Centre ◽

Open Label ◽

Safety And Efficacy ◽

Rare Tumours

IntroductionLimited clinical studies have been conducted on rare solid tumours, and there are few guidelines on the diagnosis and treatment, including experiences with targeted therapy and immunotherapy, of rare solid tumours in China, resulting in limited treatment options and poor outcomes. This study first proposes a definition of rare tumours and is designed to test the preliminary efficacy of targeted and immunotherapy drugs for the treatment of rare tumours.Methods and analysisThis is a phase II, open-label, non-randomised, multiarm, single-centre clinical trial in patients with advanced rare solid tumours who failed standard treatment; the study aims to evaluate the safety and efficacy of targeted drugs in patients with advanced rare solid tumours with corresponding actionable alterations, as well as the safety and efficacy of immune checkpoint (programmed death receptor inhibitor 1, PD-1) inhibitors in patients with advanced rare solid tumours without actionable alterations. Patients with advanced rare tumours who fail standardised treatment and carry actionable alterations (Epidermal growth factor receptor (EGFR) mutations, ALK gene fusions, ROS-1 gene fusions, C-MET gene amplifications/mutations, BRAF mutations, CDKN2A mutations, BRCA1/2 mutations, HER-2 mutations/overexpressions/amplifications or C-KIT mutations) will be enrolled in the targeted therapy arm and be given the corresponding targeted drugs. Patients without actionable alterations will be enrolled in the PD-1 inhibitor arm and be treated with sintilimab. After the patients treated with vemurafenib, niraparib and palbociclib acquire resistance, they will receive combination treatment with sintilimab or atezolizumab. With the use of Simon’s two-stage Minimax design, and the sample size was estimated to be 770. The primary endpoint of this study is the objective response rate. The secondary endpoints are progression-free survival in the targeted treatment group and single-agent immunotherapy group; the duration of response in the targeted therapy and single-agent immunotherapy groups; durable clinical benefit in the single-agent immunotherapy group; and the incidence of adverse events.Ethics and disseminationEthics approval was obtained from the Chinese Academy of Medical Sciences (ID: 20/132-2328). The results from this study will be actively disseminated through manuscript publications and conference presentations.Trial registration numbersNCT04423185; ChiCTR2000039310.

Download Full-text