On October 7, 2021 -Gennao Bio, a privately-held genetic medicines company developing first-in-class, targeted nucleic acid therapeutics, reported new preclinical data for its gene monoclonal antibody (GMAB) platform technology was presented as a virtual poster presentation at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) (Press release, Gennao Bio, OCT 7, 2021, View Source [SID1234590950]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The results presented demonstrate GMAB’s ability to systemically target and deliver an RNA payload to central nervous system (CNS) tumors in a mouse model of human medulloblastoma (DAOY). Studies conducted with fluorescently labeled GMAB show that the antibody readily penetrates into the central nervous system, and is quickly internalized and retained by tumors. Additional studies combining GMAB with 3p-hpRNA, a known activator of the immune signaling RIG-I pathway, show more than 50% reduction in intracranial tumor burden and suppression of spinal metastases following a single dose.

"The results presented today further reinforce the potential of our GMAB platform in oncology and support continued advancement. We look forward to nominating our first clinical program by the end of the year," said Stephen Squinto, Ph.D., chief executive officer and chair of the board of Gennao Bio.

"Treating CNS tumors systemically is challenging given the need to cross the blood-brain barrier and often requires the use of complicated formulations and invasive methods of delivery," said Peter M. Glazer, M.D., Ph.D., Chair of the Department of Therapeutic Radiology, Professor of Genetics and Robert E. Hunter Professor of Therapeutic Radiology at the Yale School of Medicine. "These promising results highlight a novel, non-invasive, targeted approach for the systemic delivery of immunostimulatory RNAs to multiple tumors, offering the potential for improved treatments options over current approaches."

The full abstract and poster presentation can be accessed on the AACR (Free AACR Whitepaper)-NCI-EORTC conference website.

On October 7, 2021 Immunome, Inc. (Nasdaq: IMNM), a biopharmaceutical company that utilizes its human memory B cell platform to discover and develop first-in-class antibody therapeutics, reported made an oral poster presentation on the company’s anti-interleukin-38 monoclonal antibody program at the joint meeting of the 2021 AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper), held October 7-10, 2021 (Press release, Immunome, OCT 7, 2021, View Source [SID1234590948]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The presentation highlighted that Immunome’s antibody:

Binds to human IL-38 and inhibits binding to its putative receptors, IL1RAPL1 and IL-36R.
Inhibits IL-38-mediated suppression of myeloid cell activity in vitro.
Leads to inhibition of tumor growth in two different murine syngeneic tumor models treated with the antibody and induces protection following implantation of secondary tumors.
"Our data support the hypothesis that blockade of IL-38, which appears to act as an innate immune checkpoint, could reverse suppressive mechanisms in the tumor microenvironment and may contribute to the treatment of multiple cancers with high unmet need," said Purnanand Sarma, PhD, President & CEO of Immunome. "Our compelling preclinical data demonstrate the power of Immunome’s platform to identify novel anti-tumor targets, such as IL-38."

Presentation Details

Title: "IMM20324, a first-in-class, anti-interleukin-38 monoclonal antibody, rescues myeloid cell activation in vitro and induces robust anti-tumor responses in vivo."

Authors: John P. Dowling, Pavel A. Nikitin, Fang Shen, James P. Finn, Nirja Patel, Cezary Swider, Jamie Steele, Halley Shukla, Matthew K. Robinson, Karen Lundgren & Benjamin C. Harman

Abstract Number: LBA022

Date/Time: All poster presentations are made available by the conference at the opening of the meeting on October 7, 2021, at 9:00am E.T.

About IL-38

Interleukin-38 (IL-38) is a member IL-1 family cytokines and antagonizes multiple proinflammatory pathways through its putative receptors IL-36R, IL1RAPL1, and IL-1R1. Ablation of the IL-38 gene in multiple autoimmune diseases models leads to delayed resolution of inflammation and exacerbation of disease. On the contrary, treatment with recombinant IL-38 leads to amelioration of inflammation. IL-38 is expressed in multiple cancer cells, especially under apoptotic conditions1. In lung adenocarcinoma patients, high IL-38 protein expression in tumor is associated with poor prognosis, high expression of PD-L1, and reduced infiltration of CD8+ T cells2. IL-38 is believed to be a key immune inhibitory cytokine in tumor microenvironment. Therefore, blockade of IL-38 is a potential therapeutic strategy to boost anti-tumor immune response. Immunome is developing an anti-IL-38 antibody therapeutic designed to block human IL-38 and potentially provide clinical benefit in multiple cancers .

1Mora J et al., Journal of molecular cell biology. 2016 Oct 1;8(5):426-38.
2Takada K et al., PLoS One. 2017 Jul 20;12(7):e0181598.

On October 7, 2021 The University of Texas MD Anderson Cancer Center and Schrödinger, Inc. (Nasdaq: SDGR), whose physics-based software platform is transforming the way therapeutics and materials are discovered, reported a two-year strategic research collaboration focused on accelerating and optimizing the development of Schrödinger’s WEE1 inhibitor program, an investigational therapeutic approach designed to target the WEE1 kinase (Press release, MD Anderson, OCT 7, 2021, View Source [SID1234590947]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The collaboration brings together the translational research and drug development expertise of MD Anderson’s Therapeutics Discovery division with Schrödinger’s expertise and drug development program for WEE1 inhibitors. The goal of the collaboration is to accelerate and optimize the clinical development path for Schrödinger’s WEE1 program through molecular biomarker-driven tumor type prioritization and patient stratification and to validate biomarkers to predict response or resistance to a WEE1 inhibitor. The joint team will seek to prioritize clinical studies of a WEE1 inhibitor as a single agent in selected cancer indications and in rational combinations for defined clinical subpopulations.

"We are excited to work with MD Anderson’s researchers to speed the development of our WEE1 program and potentially advance a new therapeutic option for patients," said Karen Akinsanya, Ph.D., executive vice president, chief biomedical scientist and head of discovery research and development at Schrödinger. "We have identified multiple highly selective WEE1 inhibitors with desirable drug-like properties that show strong pharmacodynamic responses and anti-tumor activity in preclinical models. We believe this profile may position our compounds as ideal candidates for applications both as monotherapy and as combination therapy partners."

Under the preclinical collaboration agreement, Schrödinger will join forces with researchers in MD Anderson’s Translational Research to AdvanCe Therapeutics and Innovation in ONcology (TRACTION) platform, which leads cutting-edge translational biology research to rapidly position new therapies for clinical trials. TRACTION is a core component of MD Anderson’s Therapeutics Discovery division, an integrated team of clinicians, researchers and drug development experts working to advance impactful therapies that address patient needs.

"Targeting WEE1, a critical gatekeeper of the cell cycle, is showing promise as a therapeutic strategy for treating certain cancers with select genetic alterations," said Timothy Heffernan, Ph.D., executive director of TRACTION. "Through our collaboration with Schrödinger, we aim to identify clinically relevant patient populations that may benefit from WEE1 inhibition and to advance innovative targeted therapies that can improve their lives."

MD Anderson and Schrödinger will jointly pursue translational studies, and Schrödinger will provide research support funding. As part of the agreement, MD Anderson is eligible to receive certain payments based on the future development and commercialization of Schrödinger’s WEE1 inhibitor compounds. Schrödinger will have sole responsibility for the development, manufacture and commercialization of all compounds and products, and sole rights to all novel intellectual property that arises from this collaboration.

WEE1 is a gatekeeper checkpoint kinase that prevents progression through the cell cycle, allowing time for DNA repair to occur before cell division takes place. Thus, inhibition of WEE1 allows for accumulation of DNA damage, triggering DNA breakage and apoptosis in tumor cells. Schrödinger is developing tight-binding, selective WEE1 inhibitors with optimized physicochemical properties designed to be well suited for combinations with other DNA damage response therapies for the treatment of a broad range of solid tumors.

On October 7, 2021 Boundless Bio, a next-generation precision oncology company developing innovative therapeutics directed against extrachromosomal DNA in aggressive cancers, reported that it will present a poster at the AACR (Free AACR Whitepaper)-NCI-EORTC Virtual AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) (Press release, Boundless Bio, OCT 7, 2021, View Source [SID1234590946]). The poster, LBA005: Detection of KRAS amplification on extrachromosomal DNA (ecDNA) upon acquired resistance to KRASG12C inhibitors, is available to registered attendees starting at 9AM EST today.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"Over the past decade, targeted therapies have delivered significant health improvement to patients with oncogene-driven cancers, with KRASG12C inhibitors being the most recent example," said Zachary Hornby, President and Chief Executive Officer of Boundless Bio. "Despite the use of potent inhibitors against oncodrivers like KRAS, resistance inevitably emerges. ecDNA driven oncogene copy number amplifications, a mechanism that is distinct from second site mutations, is a frequent cause of resistance in cancer cells. Boundless Bio, in collaboration with the Dana-Farber Cancer Institute and Mirati Therapeutics, has shown that, in colorectal patients treated with KRASG12C inhibitors, ecDNA based amplification played an important role in resistance to KRASG12C inhibitor therapy. These results further substantiate our mission to develop novel therapeutic strategies that can address ecDNA-enabled cancers."

"We are pleased to collaborate with Boundless Bio on this important work to identify mechanisms of acquired resistance to KRASG12C inhibitors," said Dr. Mark Awad, M.D., Ph.D., Assistant Professor of Medicine at Harvard Medical School and Clinical Director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute. "There is mounting evidence that cancers rely on oncogene amplification to drive tumor growth and resistance, and some of this copy number amplification may be occurring on extrachromosomal DNA. The development of innovative therapies for ecDNA-driven cancers will hopefully provide new treatment options for our patients in the future."

Study Summary

We first confirmed the presence of ecDNA in tumor biopsy samples collected by the Dana-Farber Cancer Institute from clinical trial patients treated with the KRASG12C inhibitor, adagrasib. Analysis of next-generation sequencing (NGS) data using proprietary Boundless Bio software enabled detection of circular DNA structures encompassing the KRAS locus. Consistent with this finding, fluorescence in situ hybridization (FISH) analysis by Boundless Bio scientists confirmed the presence of KRAS amplifications on ecDNA.

Next, an in vivo study was performed to investigate whether resistance to KRASG12C inhibitor monotherapy is mediated through an ecDNA mechanism. We used a genetically modified CT26 murine colorectal cancer model expressing KRASG12C alleles. In line with recent clinical data, both adagrasib and sotorasib induced transient tumor regressions in the CT26 model that subsequently resumed tumor growth following several weeks of continuous therapy. Strikingly, in both adagrasib and sotorasib resistant tumors, bioinformatic analysis of whole-genome sequencing data and FISH analysis from isolated recurrent tumors identified high levels of ecDNA mediated amplification of KRASG12C compared to vehicle-treated samples. The kinetics of KRAS amplification on ecDNA was also determined, showing increased KRAS copy number within two weeks after initiation of KRASG12C inhibitor treatment. Such rapid onset of resistance after tumor regression is consistent with previous in vivo studies with other ecDNA enabled tumor models. Cultures from ex vivo experiments also maintain resistance due to KRAS amplified ecDNA. Collectively, these observations implicate ecDNA as an important mediator of resistance to KRASG12C inhibitor monotherapy.

This study, along with previously published studies, confirm the evasive dynamics of ecDNA-driven oncogene copy number amplification upon therapeutic pressure on oncodrivers such as EGFR, FGFR, and now mutant KRAS. Because ecDNA can be distributed heterogeneously throughout tumors, resistance to targeted therapies can be rapid, aggressive, and difficult to treat. Here we confirm the critical need for novel therapeutic strategies directed to the function of ecDNA within cancer cells and the urgency to bring these therapies to patients with oncogene amplified cancers.

About ecDNA

Extrachromosomal DNA ("ecDNA") are circular units of nuclear DNA found within cancer cells, and which contain highly transcriptionally active genes, including oncogenes, but are physically distinct from chromosomes and lack centromeres. ecDNA replicate within cancer cells and, due to their lack of centromeres, can be asymmetrically passed to daughter cells during cell division, leading to focal gene amplification and copy number heterogeneity in cancer. By leveraging the plasticity afforded by ecDNA, cancer cells have the ability to increase or decrease copy number of select oncogenes located on ecDNA to enable survival under selective pressures, including targeted therapy, immunotherapy, chemotherapy, or radiation, thereby making ecDNA one of cancer cells’ primary mechanisms of growth, recurrence, and treatment resistance. ecDNA are not found in healthy cells but are present in many solid tumor cancers. They are a key driver of the most aggressive and difficult-to-treat cancers, specifically those characterized by high copy number amplification of oncogenes.

On October 7, 2021 -Forma Therapeutics Holdings, Inc. (Nasdaq: FMTX), a clinical-stage biopharmaceutical company focused on sickle cell disease, prostate cancer and other rare hematologic diseases and cancers, reported positive initial results from a Phase 1 trial of its novel CBP/p300 inhibitor, the oral small molecule FT-7051, in men with metastatic castration-resistant prostate cancer (mCRPC) (Press release, Forma Therapeutics, OCT 7, 2021, View Source [SID1234590945]). Initial clinical data from the Courage Study, an ongoing first-in-human Phase 1 trial presented at the AACR (Free AACR Whitepaper)-NCI-EORTC Virtual AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper), showed an encouraging safety profile of FT-7051, as well as high specificity to the CBP/p300 pathway.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"Preliminary data from the Courage Study are promising," said Andrew J. Armstrong, M.D., principal investigator of the Courage Study, and Professor of Medicine, Pharmacology and Cancer Biology, and Director of Research at the Duke Cancer Institute Center for Prostate and Urologic Cancers. "Managing the balance between safety, tolerability and efficacy is a key element of targeting this pathway, and thus far the doses studied are achieving pharmacodynamic target engagement with acceptable tolerability."

Preliminary results reported today include data as of Sept. 1, 2021, from eight men enrolled in the trial. FT-7051 was administered in 28-day cycles, with 21 days of dosing followed by seven days of no dosing. Three patients remain on study; five patients left the study (four due to disease progression and one withdrawal of consent). The adaptive trial design is intended to efficiently explore safe and efficacious doses of FT-7051. Prior to enrollment, all of the men had received diagnoses of mCRPC, castration-levels of serum testosterone and rising levels of the biomarker prostate specific antigen (PSA) after the failure of at least two lines of therapy with an approved androgen-receptor pathway inhibitor.

The initial pharmacokinetic (PK) analysis of FT-7051 documented rapid absorption, which produced maximum blood concentrations within two hours. The 150 mg dose achieved drug concentrations that approached the predicted efficacious dose based on modeling with preclinical results. Skin biopsies of the men participating in the study demonstrated a reduction in H3K27AC, a marker of activity in the CBP/p300 pathway, the target of FT-7051.

The majority of the treatment-emergent adverse events (TEAEs) were mild or moderate, at Grade 2 or lower, with no events leading to treatment discontinuation. One patient experienced Grade 3 hyperglycemia, which was medically managed. Following a dose reduction, this patient remained on treatment and experienced an ongoing PSA decline of greater than 50% at 12 weeks and greater than 80% at 16 weeks. Based upon these safety results, dose escalation is ongoing. The trial is continuing according to its adaptive design to further understand the safety and tolerability of FT-7051, gather data on clinical response including PSA and radiographic tumor response, as well as the assessment of secondary endpoints of clinical response.

"There is substantial need for new therapies to treat those with mCRPC as they progress while on existing lines of anti-androgen or chemotherapy," said David N. Cook, Ph.D., senior vice president, Forma Therapeutics’ chief scientific officer. "Thanks to the eight patients who participated in the Courage Study to date, we have made progress in understanding the potential of CBP/p300 inhibition in prostate cancer and look forward to continuing our dose escalation study."

Presentation Details

Abstract P202: Initial Findings from an Ongoing First-in-human Phase 1 Study of the CBP/p300 Inhibitor FT-7051 in Men with Metastatic Castration-Resistant Prostate Cancer (Link)
Abstract P204: Targeting the p300/CBP Epigenetic Pathway to Overcome Hormone Therapy Resistance in Advanced Prostate Cancer
Forma continues to enroll men into the Courage Study. For more information, please visit View Source or View Source

About CBP/p300

Tumor resistance to anti-androgen therapies can arise due to mutations and other changes within the androgen receptor (AR). Androgen binds to two paired proteins in ARs, CBP and p300, in a location that is highly resistant to mutations known as the bromodomain. FT-7051 is designed to attach to the CBP/p300 bromodomain potently and selectively, which then blocks androgen binding and reduces AR activation. In preclinical studies, FT-7501 demonstrated activity in both prostate cancer models that were sensitive or resistant to the approved androgen-inhibitor medicine enzalutamide.

About Prostate Cancer

Prostate cancer is the second most frequent cancer in men globally, accounting for more than 1.4 million new diagnoses and 6.8 percent of all male cancer deaths in 2020.1 In the United States, more than 248,000 men will be diagnosed with prostate cancer in 2021, and the disease will account for more than 34,000 deaths.2 When cancer has spread beyond the prostate and surgery or radiation are not an option, first-line treatment suppresses the male hormone androgen because it can stimulate prostate cancer cell growth.3,4 This treatment, called medical castration, slows progression for about two years, but most men will develop resistance and their cancer will progress.5,6 The five-year survival rate of men with metastatic prostate cancer is 30 percent.7