On April 9, 2024 Dovetail Genomics reported the debut of its LinkPrep NGS technology, showcasing its potential for de novo detection of structural variants and chromatin topology features in cancer (Press release, Dovetail Genomics, APR 9, 2024, View Source [SID1234641960]). Through its innovative chromatin conformation approach, LinkPrep technology exhibits enhanced sensitivity in detecting translocations and intra-chromosomal rearrangements compared to conventional methods, while also identifying SNVs/InDels within a single assay. Unlike traditional Hi-C methods, LinkPrep technology offers a streamlined process, generating sequenceable libraries from initial samples in a single shift. These findings are being presented at the AACR (Free AACR Whitepaper) Annual Meeting, April 5-10, in San Diego, Calif.

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"Many clinically relevant cancer driver mutations currently go undetected by conventional methods including NGS. Chromatin conformation approaches have a unique capability that will prove to be a powerful solution to address this gap," said Mathew Easterday, Ph.D., J.D., CEO of Cantata Bio. "Because of its high sensitivity, uniform coverage, and rapid workflow, the LinkPrep chemistry is the best solution for detecting these variants. This will improve the discovery and annotation of novel drivers and mechanisms of cancer. Ultimately, this can help optimize treatment decisions and inform the care and management of cancer patients."

LinkPrep technology captures genetic variation within the context of the 3D genome, enabling simultaneous genetic and epigenetic data analyses. As such, it offers a holistic view of genetics, epigenetics, and chromatin conformation revolutionizing our understanding of how gene regulatory networks interact during cancer progression. Furthermore, the novel technology captures chromosome-scale haplotype linkage, enabling applications such as allele-resolved copy number variation, haplotype resolution of variant co-occurrence, and karyotype reconstruction in the context of a cancer genome. LinkPrep technology is fully compatible with off-the-shelf or user-defined hybrid capture panels, offering improved sensitivity over whole genome approaches.

Currently undergoing late-stage validation, Dovetail Genomics is actively seeking strategic partnerships to conduct further studies demonstrating its clinical utility across specific cancer indications.

More detailed information on the LinkPrep technology will be shared in the poster:

Poster Title: LinkPrep: a rapid, high-resolution, proximity ligation method for the detection of structural variants and chromatin topology features in cancer.
Poster Number: LB287 / 3
Location: Section 53, Board 3
Date/Time: April 9th, 9am – 12:30pm
Authors: Cory Padilla, Jonathon Torchia, Daniel Hwang, Mital Bhakta, Lisa Munding

On April 9, 2024 Flare Therapeutics Inc., a clinical-stage biotechnology company targeting transcription factors to discover precision medicines for cancer and other diseases, reported data identifying immunosuppressive cell phenotypes associated with high PPARG expression in urothelial cancer (UC) patients treated with anti-PD1 therapy in a poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2024 taking place April 5-10 in San Diego, California (Press release, Flare Therapeutics, APR 9, 2024, View Source [SID1234641959])c.

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"Translational insights from our single cell analysis shed further light on the role that PPARG expression plays in the immune cell phenotypes of advanced UC patients following anti-PD1 therapy," said Michaela Bowden, Ph.D., Chief Development Officer at Flare Therapeutics. "The ongoing study of our lead asset FX-909 – which is currently being evaluated as a monotherapy in a Phase 1 clinical study – includes an exploratory biomarker approach to assess the effect of PPARG inhibition on the innate and adaptive immune response of the patients enrolled, and may inform the ability to expand this novel treatment into a potential combination treatment strategy in the future."

The poster, titled, "PPARG-high circulating monocytes exhibit an immunosuppressive phenotype in urothelial cancer patients treated with anti-PD1," offers a comprehensive analysis of PPARG expression in peripheral blood mononuclear cells (PBMCs) of advanced UC patients. PPARG has been previously associated with immune-mediated resistance and is upregulated in a variety of immune cells such as monocytes, macrophages, and lymphocytes, where it plays a role in their maturation and function.

Flare Therapeutics scientists showed that circulating classical monocytes harboring high levels of PPARG expression exhibited an immunosuppressive phenotype in UC patients who received anti-PD1 therapy. Findings corroborate molecular real-world data presented at the SITC (Free SITC Whitepaper) 2023 Annual Meeting that demonstrated high PPARG expression in patients with muscle-invasive UC is associated with an immunosuppressive tumor microenvironment and shorter real-world progression-free survival to anti-PD1 treatment.

Additional key takeaways from the poster are as follows:

Researchers conducted single-cell RNA sequencing of PBMCs from UC patients treated with anti-PD1 therapy and healthy volunteers – evaluating over 75,000 cells and identifying nine major immune cell populations.
Among peripheral blood cells, the highest PPARG expression was observed within the classical monocyte (CM) population.
PPARG expression in circulating CMs was significantly increased in UC patients compared to healthy volunteers.
PPARG-high circulating classical monocytes in UC patients exhibit a transcriptomic profile associated with immunosuppression and M2 macrophage polarization.

On April 9, 2024 NeoImmuneTech, Inc. (NIT), a global leader in T-cell-based immunotherapy, reported a poster on a pre-clinical study that opens a new field of potential applications for NT-I7 (efineptakin alfa) (Press release, NeoImmuneTech, APR 9, 2024, View Source [SID1234641958]). The poster was presented at the 2024 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (April 5-10, 2024, San Diego, CA).

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The study explored the efficacy of NT-I7 (efineptakin alfa) in combination with FOLFOX (a combination of 5-fluorouracil, leucovorin, and oxaliplatin), a first-line standard of care (SoC) for colorectal cancer, in an animal model of colorectal cancer (MC38, C57BL/6 mice).

The study’s findings suggest a significant improvement in treatment outcomes when NT-I7 is used alongside FOLFOX, demonstrating a 69% reduction in tumor size compared to the administration of FOLFOX alone. While the overall Absolute Lymphocyte Count (ALC) in the blood was reduced by FOLFOX treatment, the number of anti-cancer specific T cells in the tumor was significantly increased in the combination group compared to FOLFOX alone.

Dr. Luke Oh, President and CEO of NeoImmuneTech said: "We are very excited by results that shows NT-I7 might be effective in combination with cytotoxic chemotherapeutic agents. As chemotherapeutic agents are still the standard of care for most early-stage cancer indications, combining NT-I7 with various chemotherapeutic agents might bring new hope to patients in situations where immuno-oncology is not used."

About Colorectal Cancer
Colorectal cancer is the third most commonly diagnosed cancer and the second most common cause of cancer-related death worldwide. It often begins with growths on the inner lining of the colon or rectum called polyps, which can change into cancer over time. Colorectal cancer affects more than 150,000 people in the US and 1.8 million people worldwide each year. Despite progress in treatment in the last decade, the 5-year survival rate is still only 63% overall and a meager 13% for patients with metastatic disease.

About NT-I7 (efineptakin alfa) (rhIL-7-hyFc)
NT-I7 (efineptakin alfa) is the only clinical-stage long-acting human IL-7, and is being developed in oncologic and immunologic indications, where T cell amplification and increased functionality may provide clinical benefit. IL-7 is a fundamental cytokine for naïve and memory T cell development and for sustaining immune response to chronic antigens (as in cancer) or foreign antigens (as in infectious diseases). NT-I7 exhibits favorable PK/PD and safety profiles, making it an ideal combination partner. NT-I7 is being studied in multiple clinical trials in solid tumors and as vaccine adjuvant. Studies are being planned for testing in hematologic malignancies, additional solid tumors and other immunology-focused indications.

On April 9, 2024 GenFleet Therapeutics, a clinical-stage biotechnology company focusing on cutting-edge therapies in oncology and immunology, reported the latest findings of GFH547, an oral panRAS (ON) inhibitor, in a late-breaking research abstract at the 2024 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, GenFleet Therapeutics, APR 9, 2024, View Source [SID1234641957]).

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GFH547 is developed with novel mechanism of action by reshaping and repurposing intracellular cyclophilin A (CypA) protein to target active RAS proteins across most wild/mutant subtypes. Preclinical data demonstrated profound panRAS inhibitory activity of GFH547 and it holds the potential to overcome adaptive and acquired resistance against SIIP (switch II pocket)-based KRAS inhibitors.

"Secondary mutations detected among subjects in clinical studies of KRAS inhibitors have paved the way for the development of future therapies, and GFH547 is anticipated as a new-generation inhibitor to combat the drug resistance. GenFleet’s KRAS G12C inhibitor (GFH925) has had its New Drug Application accepted with Priority Review Designation in China. From the first-generation KRAS inhibitor to a new-generation pan-RAS inhibitor, the continuous achievements underscore GenFleet’s insight into the development of RAS pathway targeted therapies. The top-tier development also showcases the depth of GenFleet’s cutting-edge pipeline and its value potential." stated Fusheng Zhou, Ph.D., Vice President of GenFleet’s Drug Discovery Department.

Abstract Title: GFH547: An orally bioavailable, cyclophilin A-hijacking panRAS (ON) inhibitor with broad spectrum anti-tumor activities
Abstract No.: LB165/11

The GFH547-Cyp A-RAS tripartite complex inhibits most wild/mutant subtypes of active, GTP-bound RAS proteins
GFH547 has demonstrated preliminary efficacy to inhibit RAS proteins across most subtypes including the KRAS mutant proteins commonly found in human tumors (especially harboring G12C, G12D and G12V mutations). Compared with targeting RAS proteins or the RAS-RAF complex alone, the recruitment of CypA into the tripartite complex induces more profound inhibition of RAS pathway (including the RAS proteins and their downstream interaction with RAF).

The deep inhibition of KRAS pathway was observed following a single oral administration of GFH547 in KRAS mutant CDX tumors. GFH547 also demonstrates dose-dependent anti-tumor activity and drives tumor regression in KRAS mutant tumor models.

GFH547 is superior to the mainstream SIIP-based KRAS inhibitors in overcoming adaptive and acquired resistance
GFH547 is resistant to RTK activation by EGF stimulation which attenuates potency of current mainstream SIIP-based KRAS inhibitors. It is also effective to cells carrying secondary KRAS mutations causing acquired resistance to SIIP-based KRAS inhibitors. Overall, GFH547 demonstrates promising bioavailability, kinase selectivity and safety in the preclinical research.

About RAS and GFH457
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、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.

GFH547 is a novel small-molecule panRAS (ON) inhibitor hijacking Cyp A to target active, GTP bound RAS proteins of most wild/mutant subtypes, including most commonly found KRAS mutant (G12C, G12D, G12V, etc.) proteins. Preclinical research of GFH547 demonstrates dose-dependent anti-tumor activity and drives tumor regression in multiple KRAS mutant tumor models. GFH547 is also superior to the mainstream SIIP (switch II pocket)-based KRAS inhibitors in overcoming adaptive and acquired resistance.

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.