On April 9, 2024 GenFleet Therapeutics, a clinical-stage biotechnology company focusing on cutting-edge therapies in oncology and immunology, reported the latest research findings of GFH375, an oral KRAS G12D (ON/OFF) inhibitor, at the poster presentation of the 2024 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, GenFleet Therapeutics, APR 9, 2024, View Source [SID1234641956]).

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GFH375 (VS-7375) is a highly potent and selective KRAS G12D inhibitor targeting both "ON" (GTP-bound) and "OFF" (GDP-bound) states of the protein. With preliminary safety data, favorable oral bioavailability and potent efficacy across preclinical models, GFH375 also holds the potential for treating KRAS G12D mutant cancers with brain metastases.

"G12D mutation is the most prevalent KRAS mutation detected in human carcinomas, and no G12D-targeted therapies have been approved yet. Preliminary research has shown potent efficacy and safety of orally administered GFH375 in animal models. Additionally, GenFleet’s GFH925 (KRAS G12C inhibitor) has had its New Drug Application accepted with Priority Review Designation in China. GenFleet is well-positioned to rapidly deploy its proven expertise in developing RAS pathway inhibitors to deliver more cutting-edge innovative therapies. "stated Fusheng Zhou, Ph.D., Vice President of GenFleet’s Drug Discovery Department.

Preclinical research also demonstrated the combination of avutometinib (RAF/MEK clamp) and GFH375 confers enhanced anti-tumor efficacy relative to either agent alone, indicating potential for future clinical combination. Avutometinib in combination with defactinib (FAK inhibitor) is being developed by Verastem Oncology with clinical development across multiple indications and was granted breakthrough therapy designation for the treatment of patients with recurrent low-grade serous ovarian cancer (LGSOC) regardless of KRAS status and after one more prior lines of therapy, including platinum-based chemotherapy. GenFleet entered into a discovery and development collaboration with Verastem Oncology (Nasdaq: VSTM) in 2023 to advance three oncology programs, the first program selected is GFH375.

Abstract Title: GFH375 (VS-7375): An oral, selective KRAS G12D (ON/OFF) inhibitor with potent anti-tumor efficacy
Abstract No. : 3318

Original mechanism targets both active and inactive KRAS G12D
GFH375 inhibits GTP-bound KRAS G12D and its binding with downstream proteins such as RAF; the drug candidate also targets the GDP-GTP exchange to inhibit the activation of KRAS G12D.

Potent single agent anti-tumor efficacy of GFH375 and its potential for treating KRAS G12D mutant cancers with brain metastases
GFH375 potently and selectively inhibits phospho-ERK signaling and proliferation in KRAS G12D mutant tumor cells. GFH375 also accumulates in tumor tissue and elicits sustained inhibition of the protein following a single oral administration.

GFH375 induces tumor regression in multiple KRAS G12D CDX tumor models via oral administration. It also demonstrates potent anti-tumor activity in an intracranial CDX tumor model, which suggests the potential of GFH375 as a treatment for KRAS G12D mutant cancers with brain metastases.

Combination of GFH375 and avutometinib enhances anti-tumor efficacy while retaining favorable toxicity profile in vivo
The combination of GFH375 and avutometinib enhances anti-tumor efficacy and leads to more significant tumor regression over either drug candidate alone. Meanwhile, the results exhibit favorable toxicity profile of this combination.

About RAS and KRAS mutations

RAS proteins, in active GTP-bound or inactive GDP-bound form, are binary molecular switches controlling cellular responses in signaling pathways including RAS-RAF-MEK-ERK and PI3K/AKT/mTOR. Three RAS genes encode for protein isoforms, namely Kirsten Ras (KRAS), Harvey Ras (HRAS) and Neuroblastoma Ras (NRAS), and KRAS is the most frequently mutated oncogene in humans.

About KRAS G12D and GFH375

Among KRAS mutations, G12D, G12V, and G12C represent the top three most frequently mutated alleles. KRAS G12D mutation is commonly found in pancreatic ductal adenocarcinoma, colorectal cancer, and lung adenocarcinoma. A large percentage of patients harboring KRAS G12D mutation are found without smoking history and with poor response to PD-1 inhibitors. Mutant-selective G12D inhibitor holds promise to benefit large segments of KRAS-driven PDAC patients since KRAS G12D alteration is the most frequently occurring somatic change in PDAC patients (about 40%) who are reported to have an overall 5-year survival rate lower than 10%.

GFH375 is an orally active, potent, highly selective small-molecule KRAS G12D (ON/OFF) inhibitor designed to target the GTP/GDP exchange, thereby disrupting the activation of downstream pathways and effectively inhibiting tumor cell proliferation. Preclinical studies demonstrated that the inhibition of GFH375 on tumor growth is enhanced along with the increase in dosage and duration of treatment; GFH375 also demonstrated low off-target risk in kinase selectivity and safety target assays.

GenFleet entered into a discovery and development collaboration with Verastem Oncology (Nasdaq: VSTM) to advance three novel oncology discovery programs related to RAS pathway-driven cancers. The risk-sharing structure of the collaboration provides Verastem Oncology a milestone-based option to license up to three compounds. The licenses would give Verastem Oncology development and commercialization rights outside of China while GenFleet would retain rights inside of mainland China, Hong Kong, Macau, and Taiwan.

On April 9, 2024 Jacobin Pharma (1167.HK), a clinical-stage oncology company focusing on undruggable targets, reported that the company will present the results of two preclinical evaluation of PARP7 inhibitor JAB-26766 and p53 Y220C reactivator JAB-30355 in form of the abstract during the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2024 (the "AACR 2024") from April 5 to 10, 2024 (Press release, Jacobio Pharmaceuticals, APR 9, 2024, View Source [SID1234641955]).

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Dr. Andrea Wang-Gillam, Chief Medical Officer and Global Head of R&D of Jacobio Pharma, said: " The preclinical data of the two drugs are representatives of our continued efforts in developing drugs toward key oncogenic pathways. P53 Y220C is the first tumor suppressor gene to enter into clinical study and has the potential to be used in combination with chemotherapy or oncogenic protein inhibitors. As an important downstream target of the STING signaling pathway, PARP7 is expected to be used in combination with immunotherapy in the future. Jacobio is committed to developing both assets globally."

Details for the 2024 AACR (Free AACR Whitepaper) abstracts are as follows:

JAB-26766: a small-molecule, orally bioavailable PARP7 inhibitor with high potency and selectivity
Poster Presentation: April 9, 2024, 9:00 AM – 12:30 PM (GMT-7)
Session: PO.ET09.01 – DNA Reactive Agents

JAB-26766 is a potent, orally bioavailable PARP7 inhibitor with >1800-fold selectivity on PARP7 over PARP2. JAB-26766 as a single agent shows potent in vivo anti-tumor activities, which can be further enhanced through combination with STING agonist or anti-PD-1 mAb.

JAB-30355: A highly potent, orally bioavailable p53 Y220C reactivator
Poster Presentation: April 9, 2024, 1:30 PM – 5:00 PM (GMT-7)
Session: PO.ET09.09 – Novel Antitumor Agents 4

JAB-30355 is a potent and selective p53 Y220C reactivator. JAB-30355 exhibited dose-dependent anti-tumor activity, inducing tumor stasis or regression in multiple CDX and PDX models of ovarian cancer, pancreatic cancer, gastric cancer, and small cell lung cancer, with overall good tolerability. A phase I/IIa clinical trial to evaluate the safety and efficacy of JAB-30355 in patients with advanced solid tumor is ongoing in U.S.

The 2024 AACR (Free AACR Whitepaper) Annual Meeting will be held in San Diego, California, U.S. from April 5th to April 10th. For more information, please visit the official website of the AACR (Free AACR Whitepaper): View Source

On April 9, 2024 Aadi Bioscience, Inc. (NASDAQ: AADI), a commercial-stage precision oncology company focused on developing and commercializing therapies for cancers with alterations in the mTOR pathway, reported it will present new non-clinical data that highlight the combinability of nab-sirolimus and its potential for synergy to enhance anti-cancer effects and overcome resistance (Press release, Aadi Bioscience, APR 9, 2024, View Source [SID1234641954]). These data will be presented during poster sessions at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in San Diego, CA, taking place April 5-10, 2024.

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Poster presentation details and abstract highlights include:

Title: "Evaluation of nab-sirolimus in combination with fulvestrant or PI3K pathway inhibitors to overcome resistance in breast cancer cell lines"
Presenting Author: Shihe Hou, PhD
Session Title: Reversal of Drug Resistance
Poster Number: Poster Section 25; Poster 6
Date/Time: Wednesday, April 10, 2024, 9:00 AM – 12:30 PM

Fulvestrant, the selective estrogen receptor degrader and PI3K inhibitors, such as alpelisib, have demonstrated efficacy in patients with HR+ PI3K-mutated breast cancer; however, resistance still occurs
nab-sirolimus enhanced the cytotoxic effects of fulvestrant in HR+ breast cancer cells and PI3Ki in both HR+ and HR- breast cancer cells
The addition of nab-sirolimus to endocrine therapy or PI3K-AKT-mTOR pathway inhibitors may mutually overcome mechanisms of resistance induced by single-agent treatments
These data further support the combination of nab-sirolimus with endocrine therapy for hormone-driven cancers, as is currently being investigated in patients with advanced or recurrent endometrioid endometrial cancer in a Phase 2 study (NCT05997017)
Title: "Correlation of nab-sirolimus tumor drug levels and improved tumor suppression in KRAS G12C non-small cell lung cancer xenografts treated with nab-sirolimus in combination with KRAS inhibitors"
Presenting Author: Shihe Hou, PhD
Session Title: Targeting Kinase and ERK Pathways
Poster Number: Poster Section 46; Poster 3
Date/Time: Tuesday, April 9, 1:30 – 5:00 PM

Corresponding with greater antitumor activity, nab-sirolimus was associated with higher intratumoral drug concentration and stronger mTOR target suppression than everolimus when the agents were combined with KRAS G12C inhibitors
These findings suggest more efficient tumor-targeting with nab-sirolimus plus a KRAS G12C inhibitor may lead to improved target inhibition and improved clinical outcomes

On April 9, 2024 BioCity Biopharma reported that the U.S. Food and Drug Administration (FDA) has cleared the company’s Investigational New Drug (IND) application for a Phase 1 study of BC2027 (Press release, Biocity Biopharmaceutics, APR 9, 2024, View Source [SID1234641953]). BC2027, which is BioCity’s second first-in-class antibody drug conjugate (ADC) approved for clinical development, targets Glypican 3 (GPC3), a proteoglycan found in the outer membrane of cancer cells. BioCity’s first ADC, BC3195, which is directed against another novel target called placental-cadherin (CDH3), a cell adhesion molecule that confers invasiveness and metastatic properties to cancer cells, is also in clinical trials.

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GPC3 is specifically up-regulated in the most common type of liver cancer, hepatocellular carcinoma (HCC), several types of lung and esophageal cancer, and other malignancies, although rarely or not expressed in normal liver tissues, making GPC3 a rational treatment target for cancers that express it. Recently, clinical activity has been noted with chimeric antigen receptor (CAR) T cells and other therapies targeting GPC3, demonstrating the potential of GPC3 as a therapeutic target.

BC2027 binds with very high affinity to GPC3 and efficiently internalizes into cancer cells where it releases its cancer killing payload. In addition to directly killing cancers cells in which it enters, BC2027’s cancer activity is enhanced as it kills other cancer cells indirectly via a "bystander effect". In preclinical studies, BC2027 was also quite safe and tolerable while demonstrating robust anticancer activity with greater than 90% inhibition of tumor growth in some well-established cancers. These findings indicate the potential for BC2027 to be a novel, safe, and effective cancer treatment.

The uniqueness of GPC3 as a target also suggests that BC2027 may in part overcome the challenges of cancer drug resistance. Dr. Yong Jiang Hei, CEO of BioCity, noted that "Drug resistance has increasingly become a challenge in cancer treatment. BioCity aims to develop next generation therapies with the potential to delay and overcome drug-resistance. Among different strategies, developing novel ADCs is an important approach to address the inherent drug resistance of HCC and many other cancers, as well as secondary drug resistance resulting from available anticancer therapies." He added, "Now BioCity has two first-in-class, novel ADCs in global clinical development, thereby resulting in a competitive edge as BioCity’s ADCs are clearly differentiated. The company will strive to advance the clinical development of these exciting ADC therapeutics to meet the unmet clinical needs and benefit patients worldwide as early as possible." Dr. Hei says.

HCC and GPC3

Liver cancers are highly prevalent worldwide with approximately 860,000 newly diagnosed cases and 750,000 ①deaths annually. Among liver cancers, 90% are HCC. In addition, the poor prognosis of the disease represents a significant unmet medical need.

In recent years, with the rapid development of systemic therapies for HCC, the standard of care for advanced HCC has evolved from traditional chemotherapy to multi-kinase inhibitors and immune checkpoint inhibitors, or the combination of the two. However, the efficacy of these therapies is limited and further advances in treatment are urgently needed.

GPC3 is highly expressed in more than 70% HCC and the expression level correlates with the extent of disease progression. Therefore, GPC3 is a specific tumor marker and closely related to disease prognosis, making it a promising target for the treatment of HCC②.

On April 9, 2024 MEDSIR, a leading company dedicated to the strategic design of independent clinical research, reported in the Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper), a premier event that brings together scientists, clinicians, industry professionals, advocates, and other stakeholders in the field of cancer research, presenting the results of two sub-studies focused on biomarkers: transFal, focused on patients with HR+/HER2- advanced breast cancer and METSGain, centered on patients with early breast cancer (Press release, MedSIR, APR 9, 2024, View Source [SID1234641952]).

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Both studies underscore the importance of utilizing biomarkers. Their early detection has been shown to increase patient survival rates by aiding in selecting the most appropriate treatment for patients.

In the context of personalized medicine, biomarkers are also important for tailoring treatments for individual patients based on their unique biological characteristics, allowing for more precise and effective medical interventions.

MEDSIR’s mission is to improve therapeutic responses, thereby enhancing patient lives. Through translational studies that use samples from groundbreaking trials, such as PARSIFAL and PHERGain, MEDSIR aims to elevate clinical practice for the benefit of patients.

Mario Mancino, PhD, Translational Research Manager at MEDSIR, expressed enthusiasm: "We are thrilled to present our research at the Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper). Our commitment to advancing personalized medicine through biomarkers underscores our dedication to improving patient outcomes."

These findings represent significant strides in understanding and leveraging biomarkers for personalized cancer care, offering new hope to patients and paving the way for more effective treatment strategies tailored to individual patients’ biological profiles.

transFAL: Unlocking Biomarkers for HR+/HER2- Advanced Breast Cancer

MEDSIR introduced the results of the transFAL study, aimed at uncovering biomarkers of response or resistance to palbociclib in combination with endocrine therapy-based regimens for patients with HR+/HER2- advanced breast cancer. The study, analyzing samples from the PARSIFAL trial, revealed significant insights into biomarker associations with treatment response. Notably, high expression of Ki67 and CDK6, along with elevated ctDNA density at baseline, were correlated with shorter progression-free survival and overall survival. These findings illuminate potential avenues for understanding and overcoming resistance to CDK4/6 inhibitors, marking a significant step forward in personalized cancer treatment.

METSGain: Predictive Potential in Early Breast Cancer

Additionally, MEDSIR presented findings from the METSGain study, which focused on predicting the risk of distant recurrences and understanding metastatic processes in early breast cancer, analyzing data from the PHERGain trial. The study demonstrated that HER2DX risk-score measurement after treatment and tumor surgery can provide valuable insights into future distant metastases. Notably, patients with high-risk scores at surgery and less molecular changes after anti-HER2 therapy were more likely to develop metastasis, further highlighting the potential of HER2DX tool developed by REVEAL GENOMICS S.L. in guiding treatment decisions for HER2+ early breast cancer patients.

About Breast Cancer

Breast cancer is the most frequent cancer diagnosed in women with an estimated global incidence of over 2 million new cases annually and is a heterogeneous disease with multiple clinical presentations and outcomes. Risk factors include family history, advanced age, hormone exposure, alcohol consumption, or smoking. Early diagnosis, risk prediction, and ongoing research into treatments are crucial for improving the prognosis and quality of life for those affected by this disease.