P1/2, N=39, Completed, Salma Sabbour | Active, not recruiting --> Completed

P1/2, N=19, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | N=12 --> 19

Plinabulin plus docetaxel significantly improved OS as second-line and third-line treatment in patients with advanced or metastatic EGFR wild-type NSCLC and could be considered as a new treatment option in this population.

Plinabulin in combination with nivolumab and ipilimumab was tolerable at the dose of 30 mg/m2. While the clinical responses in PD-1 resistant SCLC were limited, some patients had a long duration of response. The number of ≥grade 3 irAE with the combination were lower than expected.

MRTF-dependent increase in GEF-H1 was prevented by inhibition of the transcription factor Sp1, and mutating putative Sp1 binding sites in the GEF-H1 promoter eliminated its MRTF-dependent activation. Since the GEF-H1/RhoA axis is key for fibrogenesis, this novel MRTF/Sp1-dependent regulation of GEF-H1 abundance represents a potential target for reducing renal and cardiac fibrosis.

P1, N=18, Active, not recruiting, Lyudmila Bazhenova, M.D. | Trial completion date: Dec 2022 --> Jun 2025

P1/2, N=39, Active, not recruiting, Salma Sabbour | Trial completion date: Jan 2024 --> Jul 2024

P1/2, N=12, Recruiting, M.D. Anderson Cancer Center | Phase classification: P1b/2 --> P1/2

P1/2, N=39, Active, not recruiting, Salma Sabbour | Recruiting --> Active, not recruiting | Trial completion date: Sep 2023 --> Jan 2024

Introduction: High dose melphalan with autologous hematopoietic stem cell transplantation (AHCT) for multiple myeloma is effective for disease control, but has a period of obligate neutropenia. The addition of plinabulin to pegfilgrastim did not add major toxicities after AHCT. Patients had elevated WBC on Day +2, low rates of NENF, and potentially less need for transfusion support. Plinabulin PK, quality of life data, and PROs will be presented.

P2, N=17, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting | Trial completion date: Nov 2024 --> Nov 2025 | Trial primary completion date: Nov 2024 --> Nov 2025

These results demonstrated that circARHGEF28 abolished the degradation of LGALS3BP by sponging miR-671-5p, thus blocking the activation of the NF-κB pathway. Our findings revealed that circARHGEF28/miR-671-5p/LGALS3BP/NF-κB may be an important axis that regulates PCa progression.

P2, N=17, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Nov 2023 --> Nov 2024 | Trial primary completion date: Nov 2023 --> Nov 2024

Compound 11c also significantly induced G2/M cell cycle arrest and apoptosis in dose dependent manner. These results suggest that compound 11c might be a potential candidate for cancer treatment as antimicrotubule agent.

P1/2, N=35, Recruiting, Salma Sabbour | Trial primary completion date: Mar 2023 --> Sep 2023

Clinically, the levels of both HUNK expression and phosphorylation S645 of GEH-H1 are not only downregulated in CRC tissues with metastasis compared with that without metastasis, but also positively correlated among these tissues. Our findings highlight the importance of HUNK kinase direct phosphorylation of GEF-H1 in regulation of EMT and metastasis of CRC.

Bone marrow suppression remains a common serious risk of classical/non-classical cancer drugs. Under these conditions, the addition of Plin offers rapid protection of GMP lineage cells which can be captured by simple blood cell counts. Incorporation of blood-based biomarkers may help enrich NSCLC pts with better sensitivity to Plin/Doc combination than Doc alone.

P2, N=47, Recruiting, Peking Union Medical College Hospital | Not yet recruiting --> Recruiting | Initiation date: Nov 2022 --> Feb 2023

Our studies suggest that ARHGEF2 activation promotes neural lineage plasticity contributing to the survival and proliferation of enzalutamide-resistance and NEPC cells. ARHGEF2 could serve as a biomarker to stratify advanced prostate cancer patients for better treatment options and a potential therapeutic target in advanced prostate cancer.

This trial will provide evidence of the benefit and safety of pembrolizumab in combination with plinabulin and docetaxel in metastatic NSCLC patients who have been exposed and developed resistance to first-line PD-1/PD-L1 inhibitor either as monotherapy or in combination with chemotherapy.

These 5 candidate genes contribute to the molecular diagnosis and targeted therapy of HB. And we found "ARHGEF2-RhoA-Cyclin D1/CDK4/CDK6-EF2" is a key mechanism regulating cell cycle pathway in HB. This will be helpful in the treatment of HB. The occurrence of HB is related to abnormal TIICs. We speculated that memory B cells play an important role in HB.

Correspondingly, AR inhibition or AR antagonist treatment can restore ARHGEF2 expression, thereby allowing prostate cancer cells to induce treatment resistance and tolerance. Overall, our findings provide an explanation for the contradictory clinical results that ADT resistance may be caused by the up-regulation of ARHGEF2 and provide a novel target.

P2, N=47, Not yet recruiting, Peking Union Medical College Hospital

To fully reveal targetable gene fusions or oncogenic isoforms in melanoma, targeted RNA-based NGS can be used as a supplement to DNA-based NGS testing.

Furthermore, downregulation of ARHGEF2 gene expression suppresses cell viability and markers of neuroendocrine differentiation in enzalutamide-resistant and neuroendocrine cells. The 95 neural lineage gene signatures capture an early molecular shift toward neuroendocrine differentiation, which could stratify advanced prostate cancer patients to optimize clinical treatment and serve as a source of potential therapeutic targets in advanced prostate cancer.

P3, N=559, Completed, BeyondSpring Pharmaceuticals Inc. | Active, not recruiting --> Completed

He was started on a treatment regimen of pembrolizumab and plinabulin (a phase I microtubule inhibitor) with radiation to the liver 2 months ago...After an initial period of observation, the patient was started on oral budesonide 9 mg/d and ursodiol 1000 mg/d for empiric treatment of IMH without subsequent improvement in liver enzymes...At the end of treatment, transaminases reached >5 times ULN. No improvement was seen in liver enzymes after initiating empiric steroid therapy for suspected IMH.

In this pilot trial (NCT05130827, a single dose of 40mg of intravenous plinabulin was given on day of stem cell infusion (Day 0) in conjunction with pegfilgrastim on Day +1 after high dose melphalan and AHCT with the primary objective to reduce the period of absolute neutropenia in patients with MM. To date, plinabulin appears well tolerated, and patients have not had non-engraftment related neutropenic fevers. Enrollment is ongoing, and full trial results will be presented.

HCC cell growth was more inhibited when ARHGEF2 knockdown was paired with targeted medicines. Collectively, we uncovered a previously hidden mechanism where ARHGEF2/EDN1 pathway promotes angiogenesis and participates in ER stress-related drug resistance in HCC.

The addition of Plin to Doc was superior to SoC Doc alone for efficacy and safety in the clinically relevant subgroup of non-squamous EGFR-wild type, 2nd/3rd line NSCLC pts.

We previously reported an OS, Safety, and QTWiST benefit with Plin/Doc vs Doc alone (ESMO 2021) in EGFR wild type 2nd/3rd line NSCLC pts from DUBLIN-3. Here, we report statistically significant QoL benefits with Plin/Doc vs Doc alone, as assessed with EORTC QLQ C30 and LC13, which may be relevant to guide treatment decisions in this generally sick patient population.

In addition, the lncRNA signature was independently prognostic and potentially associated with the progression of LGG. Therefore, the 9-autophagy-related-lncRNA signature may play a crucial role in the diagnosis and treatment of LGG, which may offer new avenues for tumour-targeted therapy.

We identify a novel oncogenic epitranscriptome axis of YTHDF1-mA-ARHGEF2, which regulates CRC tumorigenesis and metastasis. siRNA-delivering LNP drug validated the therapeutic potential of targeting this axis in CRC.

P2, N=15, Recruiting, Memorial Sloan Kettering Cancer Center | Not yet recruiting --> Recruiting

P2, N=15, Not yet recruiting, Memorial Sloan Kettering Cancer Center

Here we show that RKIP inhibits cancer cell invasion and metastasis by stimulating RhoA anti-tumorigenic functions. Mechanistically, RKIP activates RhoA in an Erk2 and GEF-H1 dependent manner to enhance E-cadherin membrane localization and inhibit CCL5 expression.

We previously reported the discovery of a novel transcriptional signature and therapeutic targets for therapy resistant MM by comprehensive single cell RNA-seq analysis (scRNA-seq) of plasma cells (PCs) in patients with primary refractory MM (PRMM) enrolled in the KYDAR clinical trial (NCT04065789, carfilzomib Lenalidomide dexamethasone daratumumab for PRMM [Cohen YC, Nature Med, 2021]). Here we report scRNA-seq analysis of PCs from patients with advanced refractory MM (aRRMM) (n=21) enrolled in an ancillary sub-study of a prospective clinical trial (XPORT-MM-028, NCT04414475), treated with selinexor combined with dexamethasone (Xd, in penta-refractory MM n=7), or with bortezomib, dexamethasone (XVd, in triple-class refractory [TCR] MM n=9), 5 patients participated in the ancillary study only...Protein-protein interaction enrichment analyses revealed mRNA splicing and capping as well as nucleocytoplasmic transport as up-regulated modules in the refractory patients potentially serving as a resistance mechanism for blockade of XPO1 mediated nuclear export by selinexor. In summary, our study defines a roadmap for combining single cell RNA-seq profiling with clinical trials to stratify patients according to their level of anti-MM drug resistance, to define new biomarkers for drug resistance that may support personalized therapeutic decisions and reveal potential novel targets.

Similar results were obtained with positive controls PAK4 [PF-3578309] and NAMPT specific inhibitors [FK-866]...We then showed KPT-9274 to synergize with the standard of care chemotherapy cyclophosphamide, vincristine, and adriamycin used for NHL management (decreased IC25 and IC50 in several combination treatments)...The anti-tumor potential of KPT-9274 ± niacin in several aggressive lymphoma models strongly supports its efficacy in this setting. It strengthens our phase I study design to evaluate safety and tolerability and anti-tumor activity in patients with advanced solid malignancies or NHL (NCT02702492).

In analogy, oncogenes (e.g., LMO2, ARHGEF28, NOTCH1, RET, NOTCH2, DDR2) and tumor suppressor genes (like KMT2C, EP400, RASA2, CYLD) were enriched in synonymous mutations. A consolidated analysis of co- occurrence of both synonymous and NS mutations may help revisit their mechanistic oncogenic and clinical significance in MM.