On October 23, 2024 HotSpot Therapeutics, Inc., a biotechnology company pioneering the discovery and development of oral, small molecule allosteric therapies targeting regulatory sites on proteins referred to as "natural hotspots," reported it will present preclinical data from the Company’s mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) CARD11-BCL10-MALT1 (CBM) signalosome glue program highlighting its potential in NF-kB-driven solid tumors in a poster presentation at the 36th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium (Press release, HotSpot Therapeutics, OCT 23, 2024, View Source [SID1234647352]).

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MALT1 is a component of the CBM protein complex, which serves as a key regulator of NF-kB signaling in cells, including B and T cells. MALT1 is implicated in a range of hematological malignancies and solid tumors. Leveraging the Company’s proprietary Smart AllosteryTM platform, HotSpot has developed a potential first-in-class small molecule signalosome glue designed to selectively inhibit the scaffolding function of MALT1, a dominant driver of the NF-kB pathway, while sparing MALT1’s protease function.

"Our proprietary Smart Allostery platform has enabled the development of a MALT1 signalosome glue designed to selectively inhibit MALT1’s scaffolding function, a distinct activity profile that enables deep inhibition of the NF-kB pathway," said Geraldine Harriman, Ph.D., Chief Scientific Officer of HotSpot Therapeutics. "As the NF-kB signaling pathway is a well-characterized oncogenic driver, these preclinical data lend support for HST-1021’s potential utility for NF-kB-driven tumors, including as a precision oncology approach for solid tumors mediated by this pathway."

The presentation describes preclinical data for HST-1021, HotSpot’s MALT1 CBM signalosome glue development candidate:

In contrast to MALT1 protease inhibitors, HST-1021 demonstrated robust inhibition of CBM signalosome activity.
In an NF-kB-driven nasopharyngeal carcinoma patient-derived xenograft model, HST-1021 demonstrated dose-dependent anti-tumor activity, supporting HST-1021’s potential for the treatment of NF-kB-driven solid tumors.

On October 23, 2024 Ryvu Therapeutics (WSE: RVU), a clinical-stage drug discovery and development company focusing on novel small molecule therapies that address emerging targets in oncology, reported four posters with clinical and preclinical data from RVU305 (MTA-cooperative PRMT5 inhibitor), WRN program, ONCO Prime, and RVU120 at the 2024 EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium (ENA), October 23-25, Barcelona, Spain (Press release, Ryvu Therapeutics, OCT 23, 2024, View Source [SID1234647351]).

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"It is an exciting time for Ryvu’s pipeline as we advance a potentially best-in-class PRMT5 inhibitor, RVU305, through IND-enabling studies. We are pleased to highlight data from this program, with expected initiation of clinical development in Q4 2025, and other Ryvu projects at the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium this year. We are especially proud of our ONCO Prime target discovery platform, which demonstrates the progress of our scientific efforts on novel synthetic lethal (SL) inhibitors targeting key oncogenic drivers such as KRAS and other mutations." – said Krzysztof Brzózka, Ph.D., Chief Scientific Officer.

Upcoming Events

R&D Update at ENA 2024: webinar on Friday, October 25 at 11:00 AM CET to discuss the data presented at the ENA Symposium. To join the webcast, please register here: View Source
RVU120 Program Progress and Data Update: webinar on Thursday, December 12, 10:00 AM CET to discuss the ongoing RVU120 Phase II studies.
Poster highlights:
Poster Title: Discovery of novel MTA-cooperative PRMT5 preclinical candidate as targeted therapeutics for MTAP-deleted cancers
Poster Number: 32
Session date and time: Wednesday, October 23 (12:00-19:00 CEST)

Ryvu has developed a potentially best-in-class MTA-cooperative PRMT5 inhibitor, RVU305, demonstrating favorable drug-like properties and effective PRMT5 inhibition dependent on MTA binding.

RVU305 exhibits robust antiproliferative activity in MTAP-null cancer models, including over 100% tumor growth inhibition (TGI) at several dose levels and multiple complete remissions (CRs) at several dose levels in a DoHH2 MTAP-deleted model.
Tolerability and selectivity towards MTAP-deleted cells was also demonstrated in in vitro and in vivo preclinical models.
Overall, the findings highlight the potential of RVU305 preclinical candidate as a promising therapeutic option for patients with MTAP-deleted cancers.
Poster Title: Exploring synthetic lethality and novel drug combinations in patient-derived cells
Poster Number: 417
Session date and time: Friday, October 25 (09:00-15:00 CEST)

Ryvu has developed a proprietary platform, ONCO Prime, to discover novel synthetic lethal (SL) inhibitors targeting key oncogenic drivers such as KRAS and other mutations.

Initial data are presented in colorectal cancer (CRC), but the platform has the potential to discover novel SL targets across all tumor types. ONCO Prime uses human intestinal stem cell (hISC)-derived cancer model cells, patient-derived xenografts (PDXs), and clinical samples to conduct genomic and functional analyses.
Ryvu generated isogenic cancer models and validated them through transcriptomic profiling of patient-derived xenografts (PDXs) and patient-derived cell cultures to ensure clinical relevance.
The data presented in this poster highlights the outcomes of chemical compound and CRISPR/Cas9 screenings, confirming the reliability and relevance of our model for identifying new therapeutic targets in oncology.
Poster Title: Discovery of WRN inhibitors as targeted therapy in the treatment of microsatellite unstable (MSI-H) tumors
Poster number: 107
Session date and time: Wednesday, October 23 (12:00-19:00 CEST)

Ryvu is developing a series of potent and selective WRN helicase inhibitors that demonstrate pronounced efficacy in tumors with high microsatellite instability (MSI-H).

Ryvu WRN inhibitors show nanomolar potency in viability assays in MSI-H cell lines, with excellent selectivity over microsatellite-stable (MSS) cells.
In in vivo studies, Ryvu inhibitor strongly suppressed tumor growth in an MSI-H model (SW48) while not impacting the MSS model (SW620).
The compounds exhibit favorable pharmacokinetics, achieving optimal exposure and target engagement, further enhancing their therapeutic potential in MSI-H cancers.
Poster Title: Phase I/II trial of RVU120, a CDK8/CDK19 inhibitor in patients with relapsed/refractory metastatic or advanced solid tumors
Poster Number: 34
Session date and time: Wednesday, October 23 (12:00-19:00 CEST)

RVU120 is being tested in patients with solid tumors in an ongoing Phase I/II clinical trial, AMNYS-51. RVU120 has demonstrated a manageable safety profile across multiple dose levels and dosing schedules in patients with advanced or metastatic solid tumors.

No dose-limiting toxicities (DLTs) were observed, and most treatment-emergent adverse events (TEAEs) were mild to moderate, with nausea and vomiting being the most common.
6/8 patients with adenoid cystic carcinoma achieve a longer duration of treatment on RVU120 compared with their most recent prior line of therapy. A reduction of 20% of target lesions was observed in 2 patients with adenoid cystic carcinoma.
The recommended phase 2 dose (RP2D) for the QOD schedule was identified as 250 mg and remains the primary dosing schedule in clinical studies, but a continuous dosing schedule was explored and could offer an alternative to patients: continuous every day administration (QD) of RVU120 at doses of 100 mg and 150 mg is considered safe and may improve tolerability of RVU120 compared with 250 mg every other day.

On October 23, 2024 Tyra Biosciences, Inc. (Nasdaq: TYRA), a clinical-stage biotechnology company focused on developing next-generation precision medicines that target large opportunities in Fibroblast Growth Factor Receptor (FGFR) biology, reported that it will host a conference call and webcast on October 25, 2024 at 8:00 am ET to share interim clinical results of TYRA-300 from the SURF301 Phase 1/2 study in metastatic urothelial cancer (mUC) (Press release, Tyra Biosciences, OCT 23, 2024, https://www.prnewswire.com/news-releases/tyra-biosciences-to-host-conference-call-on-interim-clinical-data-of-tyra-300-from-surf301-phase-12-study-on-october-25-2024-at-8am-et-302285111.html [SID1234647350]). These data will be presented in a late-breaking oral presentation at the 36th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) (ENA) Symposium on Molecular Targets and Cancer Therapeutics, being held October 23-25, 2024, in Barcelona, Spain.

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Gary Steinberg, MD, Professor of Urology, Department of Urology, Rush University Medical Center, will be joining members of TYRA’s management team on the call and will be available during Q&A.

Conference Call Information

TYRA is hosting a conference call and webcast on October 25, 2024, at 8am ET to review the interim clinical data demonstrated with TYRA-300 in mUC. Participants may access a live webcast of the call and the associated slide presentation on the "For Investors" page of the TYRA website at View Source To participate via telephone, please register in advance at this link. Upon registration, all telephone participants will receive a confirmation email detailing how to join the conference call, including the dial-in number along with a unique passcode and registrant ID that can be used to access the call. A replay of the conference call and webcast will be archived on the Company’s website for at least 90 days.

On October 23, 2024 GRAIL, Inc. (Nasdaq: GRAL), a healthcare company whose mission is to detect cancer early when it can be cured, reported early results from the REFLECTION study, which aims to understand the real-world experience of the Galleri multi-cancer early detection (MCED) test in routine clinical settings (Press release, Grail, OCT 23, 2024, View Source [SID1234647349]). The Galleri test is recommended for adults with an elevated risk for cancer, such as those age 50 or older. In this study, a diverse population of veterans from U.S. Department of Veterans Affairs (VA) sites with toxic exposure but with no symptoms suggestive of cancer were included in study enrollment. Initial results showed that among study participants, the veteran cohort had a cancer signal detection rate consistent with other populations that have received the MCED test. The findings were presented during a presentation at the 2024 Early Detection of Cancer Conference (EDCC).

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Overall, the cancer signal detection rate in this veteran cohort was 1.30% (37/2854 participants; 95% CI: 0.94% – 1.78%), which is consistent with other populations that have received the MCED test (0.88%1 and 0.95%2). Among the 37 participants with a Cancer Signal Detected (CSD) at the time of analysis, 28 completed 180 days of follow-up, and of these, 12 cancer diagnoses were confirmed. More than half of the cases were identified at early stages (I-III) and the most common cancer signal of origin prediction was lung cancer (7). A positive predictive value (PPV), meaning that the test accurately detects a signal for cancer in someone that has cancer, was 42.9%, which is consistent with PPVs from previous Galleri testing datasets.1,3 Additional cancers could be diagnosed during the remainder of the one-year follow-up period.

"While today doctors screen individually for five specific cancers, nearly 70% of cancers have no recommended screening tests. With 50,000 veterans diagnosed with cancer every year, these initial findings from REFLECTION showing a consistent cancer signal detection rate among the veteran cohort suggest that when added to recommended screenings, MCED tests like Galleri may address an unmet medical need," said Charles Atwood, M.D., pulmonologist and lead researcher on the REFLECTION study at VA Pittsburgh. "We look forward to longer-term data that will provide veteran-reported experience with MCED testing and cancer outcomes that may provide additional insights for veterans with service-related toxic exposures."

The REFLECTION study (NCT05205967) is a multi-center, prospective, non-interventional, cohort study designed to understand the real-world experience of Galleri in clinical settings. This initial analysis included data from seven VA sites with 180 days of post-test follow-up. A total of 2,924 veterans were enrolled in the study at the time of the analysis and 2,854 are analyzable in these initial study data. Within the veteran cohort with data, 70% of participants had been exposed to one or more toxic environmental or occupational hazards during their service, including open burn pits/airborne hazards, Gulf War-related exposures, Agent Orange, radiation and others. The study included recruitment of veterans aged ≥22 years. The mean age of the cohort was 60 years old and the cohort was 79% male.

"With many veterans at elevated risk of developing cancer, the initial results from the REFLECTION study provide important insights into the impact of MCED testing to help transform early cancer detection in a real-world setting," said Josh Ofman, MD, MSHS, President at GRAIL. "We’re honored to be working with the VA, the largest national integrated health system in the U.S., to evaluate how Galleri can screen for many of the deadliest cancers before they become symptomatic, when there may be more treatment options."

About the REFLECTION Study
REFLECTION is a multi-center, prospective, non-interventional, cohort study that will enroll approximately 17,000 individuals who have opted to be screened with the Galleri, multi-cancer early detection (MCED) test in routine clinical settings. The purpose of the study is to understand the real-world experience of Galleri in clinical settings. Patients who have been prescribed the Galleri test as part of medical care by their healthcare provider will have the opportunity to consent for participation into this data collection study and will be actively followed for 12 months from the time of enrollment through data capture from electronic health records and periodic self-report questionnaires.

On October 23, 2024 J INTS BIO, a leader in oncology drug development, reported that it has revealed interim preclinical results of its second-generation synthetic HSP90 inhibitor, JIN-001, at the ENA (EORTC-NCI-AACR) (Free EORTC-NCI-AACR Whitepaper) Symposium held in Barcelona, Spain, from October 23-25, 2024 (Press release, J INTS BIO, OCT 23, 2024, View Source [SID1234647347]). The findings demonstrate JIN-001’s potential as a new therapeutic option for cancer patients who have developed drug resistance after treatment, representing a significant advancement in addressing this critical challenge.

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JIN-001: A Novel Approach to Overcoming Chemotherapy Resistance in Ovarian Cancer

Ovarian cancer remains one of the most aggressive and lethal gynecological malignancies, with approximately 70% of patients diagnosed at an advanced stage. While many patients initially respond to standard chemotherapy, drug resistance eventually develops, leading to disease progression and cancer relapse. JIN-001 was designed to address this issue and by targeting heat shock protein 90 (HSP90), a molecular chaperone that plays a crucial role in enabling cancer cells to adapt to therapeutic stress and survive.

By inhibiting HSP90, JIN-001 disrupts the ability of cancer cell to evolve and acquire resistance to the chemotherapy, thereby maintaining the effectiveness of existing standard treatment options. The preclinical studies presented at the symposium specifically explored the drug’s efficacy when used in combination with established chemotherapeutic agents, offering new hope for patients with drug-resistant cancer.

A New Therapeutic Hope for Cancer Patients

The preclinical study was designed to evaluate the efficacy of JIN-001 in ovarian cancer cell lines, including those resistant to common chemotherapies such as paclitaxel and cisplatin. Researchers treated both normal ovarian cancer cell lines and chemo resistant strains with various concentrations of JIN-001, either alone or in combination with paclitaxel (PTX) or cisplatin (Cis).

Study Highlights:

Cell Lines Tested: Ovarian cancer cell lines (OV90, TOV21G, OVCAR3) and chemo resistant cell lines (OV90/PTX200, TOV21G/PTX100, OVCAR3-CisR) were used to assess the drug’s efficacy.
Methods: The researchers measured cell viability, comparing outcomes between monotherapy with JIN-001 and combination therapy with standard chemotherapy agents.
JIN-001: A Game-Changer in the Treatment of Cancer

Combination Therapy with Chemotherapeutics: The most notable results emerged when JIN-001 was combined with conventional chemotherapy agents. When JIN-001 was used alongside paclitaxel, the IC50 value of paclitaxel in the resistant OV90/PTX200 cell line decreased from 0.204 μM to 0.043 μM, demonstrating a substantial improvement in therapeutic efficacy. Similarly, in the cisplatin-resistant OVCAR3-CisR cell line, the combination of JIN-001 with cisplatin reduced the IC50 of cisplatin from 9.643 μM to 0.142 μM.

JIN-001: A Breakthrough for Treatment-Resistant Ovarian Cancer

The interim results strongly suggest that JIN-001 has the potential to serve as a breakthrough companion therapy for patients with ovarian cancer. By inhibiting HSP90, JIN-001 enhances the efficacy of existing chemotherapies by limiting the adaptability and heterogeneity of cancer, thereby removing their ability to overcome the therapies.

"The synergy observed between JIN-001 and standard chemotherapy agents is extremely promising. It represents a new treatment paradigm for cancer patients," commented the J INTS BIO research team. "We are committed to further clinical development of JIN-001 to validate its efficacy and safety, and we believe this drug could offer a transformative option in limiting chemotherapy resistance."

JIN-001: Leading the Way in Innovative Cancer Therapies

JIN-001 has shown considerable promise as a novel therapeutic agent, particularly for chemotherapy resistance. J INTS BIO is committed to accelerating the clinical development of JIN-001, with plans to advance its use not only in ovarian cancer but also in other cancers, such as glioblastoma. Collaborative research with MD Anderson Cancer Center on JIN-001’s potential in glioblastoma has already yielded positive preclinical results, with a Phase 1 trial anticipated in 2025.