On April 8, 2025 Researchers at City of Hope, one of the largest and most advanced cancer research and treatment organizations in the U.S. with its National Medical Center named top 5 in the nation for cancer by U.S. News & World Report, have identified a new molecular target for treating pancreatic cancer, reported a Gastroenterology study published today (Press release, City of Hope, APR 8, 2025, View Source [SID1234651846]).

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Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest human cancers worldwide because it evades most treatments. With few therapeutic options, 90% of these patients don’t survive beyond five years. Now an innovative new approach offers the potential for transforming the genetic culprit behind PDAC’s stubborn resistance to treatment into a therapeutic ally.

Led by Mustafa Raoof, M.D., M.S., City of Hope assistant professor of surgery, cancer genetics and epigenetics, scientists focused on transcription-replication conflicts (TRCs), which occur when the mechanisms responsible for gene expression and genome duplication collide. The clash disrupts cells’ ability to read and copy genes, leading to replication stress, a frequent phenomenon in pancreatic cancer. The added stress causes cells to make errors copying their DNA, enabling cancer to gain a foothold and spread.

"Transcription-replication conflicts are an important vulnerability of pancreatic cancer," said Dr. Raoof, senior author of the new study. "Our study is the first to confirm proof of concept for whether exploiting this chink in cancer’s armor could provide an effective therapeutic target for patients."

In an earlier study, Dr. Raoof and his colleagues had identified high levels of TRCs as a unique weakness in pancreatic cancers that are driven by a common gene mutation. Building upon this research, his team used an experimental drug developed at City of Hope called AOH1996 as a tool to target TRCs and measure clinical responses.

First, the laboratory tested AOH1996 on a mouse model for pancreatic cancer and on small, lab-grown versions of human organs called organoids. The scientists discovered that the drug slowed tumor growth, damaged tumor cells without harming healthy tissue and boosted mouse survival from a median of 14 days to three weeks.

Next, the team tested the approach on two patients whose pancreatic tumors had resisted earlier treatments (NCT05227326). The patients experienced up to a 49% shrinkage in their liver metastases after taking the pill twice a day for two months.

Overall, the experimental approach was most effective at killing cancer cells with high replication stress, a common phenomenon that occurs when the KRAS gene goes awry in 95% of patients with pancreatic cancer.

"While the KRAS mutation has suggested a strong therapeutic target, pinpointing it in human PDAC has been difficult until now," said Dr. Raoof. "With inhibitors to mutant KRAS entering clinical trials, resistance is expected. It’s crucial for us to develop new approaches that target dependency on KRAS."

Targeting TRCs enabled the scientists to pinpoint only pancreatic cancer cells that experienced high levels of replication stress.

"Transcription-replication conflicts are more prevalent in cancer cells than normal cells," Dr. Raoof said. "Therapies that interfere with how cells manage their DNA during replication could open up new ways to treat cancer, offering hope for patients who have not benefited from other approaches."

Though excited by the study’s early results, Dr. Raoof emphasized caution in interpreting its findings. Due to the trial’s small size, scientists will need to pursue larger clinical and biomarker discovery studies to realize the full potential of therapeutic targeting of TRCs.

A respected birthplace for biotech, City of Hope created the technology that led to the development of synthetic human insulin. City of Hope later contributed to the development of "smart" cancer drugs like Herceptin, Rituxan and Avastin.

City of Hope’s Linda Malkas, Ph.D., discovered and developed AOH1996, which is exclusively licensed to the biotechnology company RLL, LLC.

Last year City of Hope received a historic $150 million gift to fund pancreatic cancer research from two entrepreneur-philanthropists: A. Emmet Stephenson Jr. and his daughter, Tessa Stephenson Brand. The donation’s mission is to accelerate leading-edge research into effective pancreatic cancer treatments through scientific partnerships with the world’s top researchers, regardless of institutional affiliation.

The Gastroenterology study entitled, "Therapeutic Targeting of Oncogene-induced Transcription-Replication Conflicts in Pancreatic Ductal Adenocarcinoma" was supported by grants from the National Comprehensive Cancer Network and the 2020 Pancreatic Cancer Action Network Career Development Award in Memory of Skip Viragh (20-20-RAOO) to the Raoof laboratory, as well as by the National Cancer Institute of the National Institutes of Health (P30CA033572) and NCCN Foundation.

On April 8, 2025 Rondo Therapeutics, a privately held biopharmaceutical company pioneering the development of next-generation T cell-engaging bispecific antibodies for the treatment of solid tumors, reported the publication detailing the discovery and preclinical development of RNDO-564, a CD28 x Nectin-4 bispecific antibody in the Journal for ImmunoTherapy of Cancer (JITC) (Press release, Rondo Therapeutics, APR 8, 2025, View Source [SID1234651847]).

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CD28 co-stimulatory bispecific antibodies are designed to boost T cell-mediated tumor killing and overcome T cell exhaustion in the solid tumor microenvironment. The publication describes the identification of a diverse panel of CD28-targeting binders with a range of potencies. Utilizing this panel, RNDO-564 was designed with optimal potency to elicit robust, safe, and durable tumor killing activity both in vitro and in vivo.

The full article, titled "A Potency-optimized CD28-activating Bispecific Antibody for the Targeted Treatment of Nectin-4 Positive Cancers," is available online at JITC.

Key findings for RNDO-564

Elicits robust Nectin-4 and signal-1 dependent T-cell mediated killing of Nectin-4-expressing tumor cells.
Enhances T-cell function in settings with mixed Nectin-4 positive and negative target cells.
Restores tumor cell killing function of serially stimulated T cells in vitro.
Fully eliminates established tumors in in vivo mouse model as monotherapy and in combination with a checkpoint inhibitor.
Preliminary tolerability studies in non-human primates demonstrate safety and support clinical evaluation of RNDO-564.
Demonstrates robust cytotoxic activity against bladder cancer cells that are resistant to antibody drug conjugates.
"The data serve as proof-of-concept for Rondo’s immune engager platform for solid tumors," said Starlynn Clarke, Senior Director of Preclinical Biology of Rondo Therapeutics. "We are excited about the clinical potential of CD28 T-cell engagers as a new modality for solid tumors, as they address the limitations of CD3 T-cell engagers, ADCs, and checkpoint inhibitors."

Rondo’s immune-engager platform delivers bispecific antibody therapeutics tailored to specific tumor targets, indications, and treatment regimens, offering a transformative alternative to traditional "one size fits all" strategies, unlocking the potential for durable responses in patients with solid tumors.

On April 8, 2025 Kura Oncology, Inc. (Nasdaq: KURA, "Kura"), and Kyowa Kirin Co., Ltd. (TSE: 4151, "Kyowa Kirin"), reported Kura submitted a New Drug Application (NDA) for ziftomenib, a highly selective, once-daily, oral, investigational menin inhibitor, for the treatment of adult patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) with a nucleophosmin 1 (NPM 1) mutation to the U.S. Food and Drug Administration (FDA) on March 31, 2025 (Press release, Kura Oncology, APR 8, 2025, View Source [SID1234651832]).

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Ziftomenib has received Breakthrough Therapy, Fast Track, and Orphan Drug Designations. The FDA has a 60-day filing review period to determine whether the NDA is complete and accepted for review; Kura expects to receive notification from the FDA on this preliminary evaluation in the second quarter of 2025. Priority Review was requested, which, if granted, would provide a target FDA review period of six months after NDA acceptance.

"This NDA submission brings us one step closer to our goal of advancing ziftomenib to market as a new therapeutic option for adult patients with R/R NPM1-m AML, a devastating disease for which there are currently no FDA-approved targeted therapy options," said Troy Wilson, Ph.D., J.D., President and Chief Executive Officer of Kura Oncology. "We look forward to working closely with the FDA throughout the review process and are optimistic about the potential of ziftomenib to impact patients with NPM1-mutant AML. We extend our gratitude to the team at Kura, our dedicated investigators, study site teams, and most importantly, to the patients who participated in our clinical trials, and their families and caregivers, who all helped make this possible. We appreciate the support and cooperation we enjoy with our partner Kyowa Kirin, and we look forward with confidence to the continued progress of this program and our collaboration."

About NPM1-Mutant AML

AML is the most common acute leukemia in adults and begins when the bone marrow makes abnormal myeloblasts (white blood cells), red blood cells, or platelets. Despite the many available treatments for AML, prognosis for patients remains poor and a high unmet need remains. The menin pathway is considered a driver for multiple genetic alterations of the disease, of which NPM1 mutations are among the most common, representing approximately 30% of AML cases. While patients with NPM1-m AML have high response rates to frontline therapy, relapse rates are high and survival outcomes are poor, with only 30% overall survival at 12 months in the R/R setting. Additionally, NPM1 mutations frequently occur with co-mutations in other disease-associated genes, including FLT3, DNMT3A, and IDH1/2, with prognosis heavily influenced by the presence of such co-occurring mutations. Adult patients with NPM1-m AML and select co-mutations and/or R/R disease have a poor prognosis, with median overall survival of only approximately 7.8 months in 2nd line, 5.3 months in 3rd line, and 3.5 months following the 4th line1. There are currently no FDA-approved therapies targeting NPM1-m AML.

About Ziftomenib

Ziftomenib is a potent and selective, oral, investigational menin inhibitor currently in development for the treatment of genetically defined AML patients with high unmet need. In April 2024, ziftomenib received Breakthrough Therapy Designation (BTD) from the FDA for the treatment of adult patients with R/R AML with a NPM1 mutation based on data from Kura’s KOMET-001 clinical trial. Additional information about clinical trials for ziftomenib can be found at www.kuraoncology.com/clinical-trials/#ziftomenib.

On April 8, 2025 Indivumed reported major milestones achieved, cementing its position as a leading oncology R&D company. Its unique, patient-centric approach to precision oncology, including data-driven AI to decipher cell biology in thousands of highly standardized cancer tissue samples, has successfully passed its proof-of-concept phase (Press release, Indivumed Therapeutics, APR 8, 2025, View Source [SID1234651833]). Numerous therapeutically novel targets and the first prototype compounds are presented, promising to significantly advance drug development in oncology. Indivumed has expanded its leadership team with Prof. Dr. Anton Wellstein as Chief Scientific Officer (CSO) and Dr. Matthias Evers as Chief Business Officer (CBO) to drive the continued growth of the company.

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Unique Approach and Unmatched Data Quality
Indivumed’s unique patient-centric R&D approach to cancer research is driven by a standardized collection process with a cold ischemia time of under 10 minutes, ensuring the integrity of tissue samples and preserving therapeutic target expression. The resulting database, IndivuType, is built on over 20 years of global clinical collaboration. It combines comprehensive multi-omics including proteomics and phospho-proteomics, and longitudinal clinical data, providing unparalleled molecular insights that are critical for oncology drug discovery.

Building on a Legacy of Excellence
IndivuType is the foundation of Indivumed’s data-driven target identification and validation process. By utilizing advanced data analytics and AI algorithms Indivumed creates a holistic view of deep and multi-modal molecular data to discover therapeutically novel targets. In addition, in-house generated patient-derived 2D and 3D cellular models, closely mimicking original tumor biology, enable effective validation of targets and reduce risk in downstream drug development.
Drug discovery activities and collaborations encompass virtual and fragment-based ligand screening, hit and lead optimization, and preclinical development, aiming to advance promising candidates toward IND. In-depth knowledge of the molecular and clinical characteristics of the targeted patient population further enables the company to support tailor-made clinical trial and patient stratification strategies at an early stage.

Deep insights leading to therapeutically novel targets
The current R&D focus lies on colorectal cancer, a disease with a high unmet medical need. Indivumed’s pipeline includes a range of targets in different stages of validation and drug discovery. Discussions with potential pharmaceutical partners are ongoing to develop hit/lead molecules towards IND and into valuable precision therapeutics.

On April 7. 2025 CureVac N.V. (Nasdaq: CVAC) ("CureVac"), a global biotech company developing a new class of transformative medicines based on messenger ribonucleic acid ("mRNA"), reported that the U.S. Food and Drug Administration (FDA) has cleared its Investigational New Drug (IND) application for a Phase 1 clinical study of CVHNLC in patients with squamous non-small cell lung cancer (sqNSCLC) (Press release, CureVac, APR 7, 2025, View Source [SID1234651815]). CVHNLC is CureVac’s investigational mRNA-based precision immunotherapy consisting of two different mRNA constructs encoding eight tumor-associated antigens (TAAs) with prevalence across sqNSCLC patients. Encoded antigens include a novel class of TAAs that have not been previously tested in cancer immunotherapy trials.

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The phase 1, dose-finding, open-label study will assess the safety and tolerability of CVHNLC plus pembrolizumab in patients with advanced sqNSCLC. The study comprises a dose-escalation part (Part A) of first-line maintenance treatment after either chemotherapy combined with pembrolizumab or pembrolizumab monotherapy. This is followed by an optional dose expansion part (Part B) in which CVHNLC is tested in combination with first-line chemotherapy and pembrolizumab.

"Immune checkpoint blockade has become a new standard of care for patients with metastatic squamous non-small cell lung cancer; however, overall prognosis still remains poor in advanced as well as in early settings of this disease, highlighting the urgent need for new therapeutic options," said Dr. Myriam Mendila, CureVac’s Chief Scientific Officer. "Squamous non-small cell lung cancer exhibits a high prevalence of shared tumor antigens among patients, presenting a unique opportunity for developing targeted off-the-shelf mRNA immunotherapies. We believe by administering CVHNLC with checkpoint inhibition, we will trigger an amplified and targeted immune response, thereby increasing the efficacy against the cancer. Our goal is to take this combination also into earlier setting of the disease."

In Part A, patients with metastatic Stage IV sqNSCLC, who have received at least three cycles of pembrolizumab, either as monotherapy or in combination with chemotherapy, will be enrolled. CVHNLC doses between 100µg and 400 µg plus pembrolizumab maintenance therapy for up to 12 months or until disease progression or undue toxicity occurs, will be administered with dose escalation. Primary endpoints include incidence of dose-limiting toxicities and treatment-related and emergent adverse events; secondary endpoints include overall response rate, progression-free survival, duration of response, and disease control rate.

"CVHNLC is our second oncology program to enter the clinical stage, highlighting the continued progress we are making with our mRNA-based precision immunotherapies. Importantly, we have been able to design CVHNLC using both known, shared tumor antigens and novel proprietary antigens discovered using our differentiated in-house technology platform," said Dr. Alexander Zehnder, Chief Executive Officer of CureVac. "We are leveraging this approach in the design of multiple novel cancer mRNA programs in our collaboration with MD Anderson Cancer Center, which we anticipate entering the clinic in the next 18-24 months."

About CVHNLC

CVHNLC has been built on CureVac’s advanced second-generation mRNA backbone, featuring two different constructs utilizing unmodified mRNA formulated in lipid nanoparticles (LNPs). Its multi-epitope design encodes eight shared antigens, four of which are well-known with established relevance in solid tumors. The other four antigens are a novel class of TAAs uniquely derived from CureVac’s proprietary whole-genome discovery platform.

About Squamous Non-Small Cell Lung Cancer

In the U.S., there are approximately 225,000 new cases of lung cancer each year, 87 % of which are NSCLC, according to the American Cancer Society. Squamous non-small cell lung cancer (sqNSCLC) represents approximately 20-30% of all NSCLC cases and is considered a more aggressive form, posing significant challenges in disease control and treatment. Patients with sqNSCLC often face a tougher prognosis compared to other types of NSCLC. In the early sqNSCLC setting after neoadjuvant treatment, there is a 30-40% relapse rate within two years, with median overall survival of 15-17 months in metastatic setting.