On April 9, 2024 Ferronova reported the initiation of a clinical trial of the company’s FerroTrace nanoparticle technology in patients with gastric and oesophageal cancers (Press release, Ferronova, APR 9, 2024, View Source;Nanoparticle-Trial-Begins-in-Patients-With-Gastric-and-Oesophageal-Cancers [SID1234641961]). It follows the completion of a first-in-human trial in 2020-2022 in oral cancer patients.

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The MAGMAP trial will enrol 60 patients and commenced today with the first patient at the Royal Adelaide Hospital, to be followed by Flinders Medical Centre and Queen Elizabeth Hospital in South Australia, and then expanding to the Peter MacCallum Cancer Centre and Austin Hospital/Olivia Newton John Cancer Centre in Victoria. Trial imaging is supported by the South Australian Health and Medical Research Institute (SAHMRI) and the National Imaging Facility.

The MAGMAP trial (Clinicaltrials.gov ID: NCT05899985) is a multi-centre, partially blinded, side-by-side comparator study to assess the safety and tolerability, feasibility, and potential added diagnostic and clinical value of FerroTrace for mapping high-risk lymph nodes in subjects.

Ferronova Chief Executive Officer Mr Stewart Bartlett said it is potentially an important study offering the promise of an innovative approach for identifying and assessing lymph nodes at high risk of containing cancer.

"Gastric, gastric-oesophageal junction, and oesophageal cancers have very poor outcomes, even where the tumour is localised to a primary location and surrounding lymph nodes where surgery is intended to be curative, and this trial is an important step to test whether our novel technology can improve outcomes in this group of patients."

Studies show following surgery, the 5-year relative survival rates for localised gastric and oesophageal cancers are approximately 74.7% and 48.5% respectively. Where the cancer has also spread to lymph nodes, the 5-year relative survival is only 34.6% and 27.7% [1][2].

Ferronova’s FerroTrace product is a super-paramagnetic iron oxide nanoparticle targeting CD206 receptors found in lymph nodes. It offers a unique targeting mechanism designed to enable a longer lymph node retention time allowing the use of MRI and a handheld surgical magnetic detector to identify and assess lymph nodes containing FerroTrace."

Principal Investigator, Dr Markus Trochsler said the trial will investigate the feasibility of mapping lymph nodes directly draining a primary tumour which theoretically have the highest risk of containing metastasis.

"Gastric and oesophageal cancers are difficult to treat due to unpredictable and extensive lymphatic drainage network in this area of the body, which means lymph nodes containing cancer could potentially be found anywhere from the neck down to the abdomen. At present, when these metastases are very small, they cannot be detected with current imaging technology" Dr Trochsler said.

"This pilot study may lead to providing us with another alternative, being a more informed treatment plan. We are testing whether nanoparticles can identify lymph nodes which are at high-risk of containing cancer cells. It will support us to progress to larger randomised trials where we will investigate tailoring our treatment approach based on the identification and position of these nodes."

Mr Bartlett said the study enrolment is predicted to take 12-15 months, and he hoped the results will lead to new methods of treating patients facing uncertain outcomes.

"The enrolment of the first patient is an important milestone for Ferronova," Mr Bartlett said.

"We are incredibly thankful for the investigators and their support teams, led by Dr Trochsler, as well as Associate Professor Kanhere at the RAH, Professor Watson and Dr Bright at Flinders, Dr Liu at the Austin and Peter Mac, and Dr Dwyer at SAHMRI. They have all put in an incredible amount of work and planning to design and initiate this trial. We look forward to seeing the results when the trial is complete."

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.