Herein, we develop macrophage cell membrane cloaked reactive oxygen species (ROS) responsive biomimetic nanoparticles, co-delivering of sonosensitizer Ce6 and JQ1 (a bromo-domain protein 4 (BRD4) inhibitor which can down-regulate PD-L1) and realizing potent GBM ISD therapy...The cascade sonodynamic and immune therapy resulted in significantly improved median survival time in both orthotopic GL261 and PTEN deficient immunosuppressive CT2A GBM mice models. Therefore, our developed biomimetic nanoparticle platform provides a promising combinational therapy strategy to treat immune suppressive GBM.

ChIP-PCR and ChIP-seq analyses revealed that histone H3 lysine 27 acetylation was enriched in the ALDH1A3 promoter in 5-Fluorouracil (5-FU)-tolerant persister PDCs. By chemical library screening, we found that the BET inhibitors OTX015/birabresib and I-BET-762/molibresib suppressed DTP-related ALDH1A3 expression and preferentially inhibited DTP cell growth...Combination therapy with 5-FU and OTX015 significantly suppressed in vivo tumor growth. These observations suggest that BET inhibitors are efficient DTP cell-targeting agents for gastric cancer treatment.

P2, N=54, Recruiting, Rahul Aggarwal | Trial completion date: Dec 2025 --> Apr 2027 | Trial primary completion date: Dec 2025 --> Apr 2027

P1/2, N=2, Terminated, Hannah Choe, MD | Completed --> Terminated; Sponsor decision

Interfering with c-Myc in established tumors using the Bromodomain and Extra-Terminal motif inhibitor JQ-1 diminished liver tumor growth in c-Jun~Fra-2 mutant mice. Thus, our data establish c-Jun~Fra-2hep mice as a model to study liver tumorigenesis and identify the c-Jun/Fra-2-Myc interaction as a potential target to improve HCC patient stratification and/or therapy.

Further, FGFR1 knockdown synergizes with BET inhibitor mediated reduction of GBM cell proliferation. Collectively, our studies suggest that co-targeting BET and FGFR1 may dampen resistance mechanisms to yield a clinical response in GBM.

These results suggest that BETi has a dual action on p21: elevating the level of p21 by inhibiting MYC and converting the oncogenic (cytoplasmic) p21 into the tumor-suppressive (nuclear) p21 by inhibiting AKT. Taken together, this study identified the synthetic lethal interaction between PTEN and BET, and provides a potential actionable target for CRC with PTEN loss.

P1/2, N=40, Enrolling by invitation, Zenith Epigenetics | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P1, N=0, Withdrawn, Bristol-Myers Squibb | Not yet recruiting --> Withdrawn

P2, N=200, Recruiting, Zenith Epigenetics | Phase classification: P2b --> P2 | Trial completion date: Sep 2024 --> Jun 2025 | Trial primary completion date: Mar 2024 --> Dec 2024

P1, N=57, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

P1, N=174, Completed, Boehringer Ingelheim | Phase classification: P1a/1b --> P1

NEDD8-activating enzyme (NAE) inhibitors, represented by MLN4924, target the only activation enzyme in the neddylation pathway that has been identified as an attractive target for cancer therapy...Together, the enhanced transcription mediated by miR-17-92 cluster inhibition and reduced degradation promoted the increase in BIM levels, resulting in a synergistic effect. Collectively, these findings highlight the need for further clinical investigation into the combination of BETi and NAEi as a promising strategy for cancer therapy.

Furthermore, following treatments such as cytarabine, a standard in AML treatment for over four decades, drug-persisting leukemic cells exhibit an enhanced reliance on mitochondrial metabolism. In this issue of Cancer Research, two studies investigated dependencies of AML cells on two respiratory substrates, α-ketoglutarate and lactate-derived pyruvate, that support mitochondrial oxidative phosphorylation (OXPHOS) following treatment with the imipridone ONC-213 and the BET inhibitor INCB054329, respectively...In summary, targeting these mitochondrial dependencies might be a promising strategy to kill therapy-naïve and treatment-resistant OXPHOS-reliant LSCs and to delay or prevent relapse. See related articles by Monteith et al., p. 1101 and Su et al., p. 1084.

A combined inhibitor of these three proteins, NEO2734, reduced the growth of both AR-positive and AR-null organoids, as measured by changes in viability, size, and composition..

Combination therapy with TAT-PiET/TAT-PiET-PROTAC and JQ1, iJMJD6, or Fulvestrant exhibits synergistic effects. TAT-PiET or TAT-PiET-PROTAC treatment overcomes endocrine therapy resistance in ERα-positive breast cancer cells. Taken together, we demonstrated that targeting the ET domain is effective in suppressing breast cancer, providing a therapeutic avenue in the clinic.

P1, N=0, Withdrawn, Northwestern University | N=34 --> 0 | Trial completion date: Dec 2031 --> Mar 2024 | Initiation date: Dec 2024 --> Dec 2023 | Not yet recruiting --> Withdrawn | Trial primary completion date: Dec 2029 --> Mar 2024

METTL3 binds to the c-Myc/WDR5 complex and promotes glycolysis, which plays a powerful role in promoting TNBC progression. Our findings further broaden our understanding of the role and mechanism of action of METTL3, and may open up new therapeutic avenues for effective treatment of TNBC with high c-Myc expression.

Additionally, knockdown of SS18-SSX, which upregulates BCL2, reduced the sensitivity to ABBV-075. These findings suggest the potential utility of BET inhibitors targeting the SS18-SSX-regulated intrinsic apoptotic pathway as a promising therapeutic strategy for SS.

Overall, BETi orchestrate an epigenetic reprogramming that leads to increased recognition of tumor cells and the killing ability of NK cells. Our results unveil the opportunity to exploit and repurpose these drugs in combination with immunotherapy.

First, the bromodomain-containing protein 4 (BRD4) inhibitor JQ1 and the cyclooxygenase-2 (COX-2) inhibitor celecoxib (CXB) were coloaded into chondroitin sulfate (CS) to obtain CS@JQ1/CXB nanoparticles (NPs). Combination treatment exhibited synergistic cytotoxicity, antimigration ability, and apoptosis-inducing and immune activation effects on TNBC cells and effectively suppressed tumor growth and metastasis in TNBC tumor-bearing mice by activating the tumor immune response and inhibiting angiogenesis. In summary, this study offers a novel combinatorial immunotherapeutic strategy for the clinical TNBC treatment.

P1, N=34, Not yet recruiting, Northwestern University | Initiation date: Dec 2023 --> Dec 2024

P1, N=41, Active, not recruiting, Dana-Farber Cancer Institute | Recruiting --> Active, not recruiting | N=66 --> 41 | Trial completion date: Jun 2025 --> Jul 2024

P1, N=42, Recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2024 --> Mar 2025 | Trial primary completion date: Mar 2024 --> Mar 2025

Based on this study, LUAD cells were susceptible to SEs inhibitors, with a reduction of cell proliferation as well as an elevation of apoptosis upon JQ1 or THZ1 intervention...Mechanistically, SMPD1-induced autophagic degradation of GPX4 assumed a crucial role in the process of ferroptosis triggered by MYEOV knockdown. Serving as an oncogene repressing ferroptosis, promoting proliferation as well as shortening survival in LUAD, SEs-mediated activation of MYEOV might distinguish as a promising therapeutic target.

P3, N=430, Active, not recruiting, Constellation Pharmaceuticals | Trial completion date: Dec 2026 --> Dec 2027

P1/2, N=216, Active, not recruiting, Bristol-Myers Squibb | Recruiting --> Active, not recruiting

P1, N=30, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting | N=22 --> 30 | Trial completion date: Jun 2024 --> Jun 2025 | Initiation date: Feb 2024 --> Nov 2024 | Trial primary completion date: Jun 2024 --> Jun 2025

P3, N=430, Active, not recruiting, Constellation Pharmaceuticals | Trial completion date: Apr 2027 --> Dec 2026

Our study reveals the critical role of IGF2BP2 overexpression mediated by SE and KLF7 in promoting HNSCC progression. Targeting SE-associated transcriptional programs may represent a potential therapeutic strategy in managing HNSCC.

NRF1 driven SPIDR transcription by occupying its SE, protecting HCC cells from oxidative stress-induced damage. NRF1 and SPIDR are promising biomarkers for targeting oxidative stress in the treatment of HCC.

JQ1 treatment resulted in down-expression of IGLL5, indicating that IGLL5 is controlled by SE...Our results suggested that IGLL5 might have a role in survival of mature B-cell tumors and involvement in MYC expression. (100 words).

P1, N=35, Completed, Constellation Pharmaceuticals | Active, not recruiting --> Completed | Trial completion date: Nov 2023 --> Feb 2024

The study suggests that the application of novel BET PROTACs in combination with chemotherapeutics could represent a new therapeutic option to improve the therapy of osteosarcomas. First orally available PROTACs have reached clinical trials.

A total of 418 differentially expressed mRNAs related to SE-lncRNAs were identified, of which 395 mRNAs had positive correlation with 12 SE-lncRNAs and 408 mRNAs had negative correlation with 15 SE-lncRNAs. JQ1 can significantly inhibit the proliferation of HeLa cells and affect the expression profile of SE-lncRNAs and mRNAs.

P1/2, N=336, Active, not recruiting, Constellation Pharmaceuticals | Trial primary completion date: Dec 2023 --> Oct 2024

In this study, we developed nanoparticles loaded with an immune checkpoint inhibitor (JQ-1) using polypyrrole/hyaluronic acid (PPyHA/JQ-1)...PPyHA/JQ-1 treatment simultaneously provides a significant tumor regression through photothermal therapy and immune checkpoint blockade, leading to a durable antitumor-immune response. Overall, our "Three-in-one" immunotherapeutic photo-activable nanoparticles have the potential to be beneficial for a targeted combinatorial treatment approach for TNBC.

P1, N=60, Recruiting, National Cancer Institute (NCI) | Initiation date: May 2024 --> Dec 2023

P1/2, N=2, Completed, Hannah Choe | Recruiting --> Completed | Phase classification: P1b/2 --> P1/2 | N=34 --> 2 | Trial completion date: Dec 2025 --> Sep 2023 | Trial primary completion date: Dec 2024 --> Sep 2023

Specifically, the immune dressing is composed of methacrylic anhydride-modified sericin (SerMA) and self-assembled nanoparticles (LJC) containing lonidamine (Lon), JQ1, and chlorine e6 (Ce6)...More importantly, the dressing generates a substantial amount of reactive oxygen species (ROS), which can effectively kill Staphylococcus aureus and promote infectious wound healing. In conclusion, this dual-function nanocomposite immune hydrogel dressing exhibits promise in preventing tumor recurrence and promoting infectious wound healing.

Moreover, genetic knockdown of MTHFD1 or application of the anti-folic acid metabolism drug methotrexate (MTX) potentiated the anti-tumor effect of JQ1 both in vitro and in vivo. Taken together, MTHFD1 as an oncogene is a potential therapeutic target for MYCN-amplified NB. The combination of MTX with JQ1 is of important clinical translational significance for the treatment of patients with MYCN-amplified NB.

Intra-articular injections of JQ1@PSLs showed prolonged retention within the joint, and remarkably reduced synovial inflammation and joint pain via suppressing M1 polarization accompanied by reduced TRPA1 expression by targeted inhibition of BRD4 in the macrophages, thus attenuating cartilage degradation during OA development. The results show that BRD4-inhibiting JQ1@PSLs can targeted-modulate macrophage polarization, which opens a new avenue for efficient OA therapy via a "Trojan horse".