On April 8, 2022 Boundless Bio, a next-generation precision oncology company developing innovative therapeutics directed against extrachromosomal DNA (ecDNA) in oncogene amplified cancers, reported that it will present a new finding at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2022, held in New Orleans and virtually from April 8-13, 2022 (Press release, Boundless Bio, APR 8, 2022, View Source [SID1234611733]). The poster, Replication stress and the inability to repair damaged DNA, the potential "Achilles’ heel" of ecDNA+ tumor cells, is available to registered attendees online starting today and for in-person presentation on April 11, 2022 at 1:30 PM – 5:00 PM CT.

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"Replication stress has long been known to be a driver of genomic instability in cancer," said Christian Hassig, Ph.D., Chief Scientific Officer of Boundless Bio. "This study demonstrates ecDNA-enabled gene amplified cancers have inherently high replication stress, thereby providing a unique point of intervention for our novel ecDNA-directed therapeutics (ecDTx). This work is an important scientific advancement both in our understanding of gene amplifications on ecDNA and in translating the science into novel therapeutics for patients with gene amplified cancers who currently have few treatment options."

Boundless Bio previously demonstrated that cancers with oncogenes amplified on ecDNA are associated with poor clinical prognosis1 and generally do not respond to targeted therapies, underscoring the urgent need to identify clinical strategies to treat ecDNA amplified cancers. For the first time, we present data showing a relationship between ecDNA and DNA replication stress, a known form of genomic instability that contributes to oncogenesis and tumor evolution. While the drivers of replication stress remain unclear, excessive replication stress leads to extensive DNA damage and cancer cell death. The results demonstrate ecDNA-enabled colorectal cancer cells have intrinsically elevated levels of replication stress and are hypersensitive to replication stress inducing agents. These novel findings highlight replication stress as a potential synthetic lethal approach in ecDNA amplified cancers.

Poster available at Boundless Bio website.

Reference
1Kim, Nguyen, Turner et al. Nature Genetics 2020

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 April 8, 2022 NiKang Therapeutics Inc. ("NiKang"), a clinical stage biotech company focused on developing innovative small molecule oncology medicines to help patients with unmet medical needs reported presentation of preclinical data investigating NKT2152’s mechanism of action, in vivo pharmacokinetic and pharmacodynamic profile, and anti-tumor effect in multiple xenograft models including ccRCC and hepatocellular carcinoma at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2022 (Press release, NiKang Therapeutics, APR 8, 2022, View Source [SID1234611732]).

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"The NKT2152 preclinical data presented today highlight its best-in-class potential with excellent potency and PK profile and support the advancement of this molecule into clinical studies," said Zhenhai Gao, Ph.D., Co-founder, President and Chief Executive Officer of NiKang. "The anti-tumor effect observed in several xenograft models suggests NKT2152 may have broader activity in other solid tumors beyond ccRCC that lack a VHL gene deficiency. We will explore such opportunities with the goal of helping more patients in need."

About NKT2152

NKT2152 is a small molecule that inhibits HIF2α. It is currently in a phase 1/2 dose escalation and expansion trial (NCT05119335). This trial is designed to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics and clinical activity in patients with advanced ccRCC. Once an appropriate dose is identified, combination studies including NKT2152 will commence.

On April 8, 2022 Affimed N.V. (Nasdaq: AFMD) ("Affimed", or the "Company"), a clinical-stage immuno-oncology company committed to giving patients back their innate ability to fight cancer, reported data from the dose escalation phase of the phase 1/2a study with the Company’s Innate Cell Engager (ICE) AFM24 as monotherapy at the Annual Meeting of the American Association of Cancer Research (AACR) (Free AACR Whitepaper) (Press release, Affimed, APR 8, 2022, View Source [SID1234611730]). A poster will be presented on April 11 during the Phase I Clinical Trials 1 session.

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The poster presentation includes data of 29 heavily pretreated patients with a variety of tumors known to express EGFR, who have received AFM24 as weekly infusions across six dose levels from 14 mg to 480 mg. AFM24 demonstrated a well-managed safety profile. The most frequent treatment-emergent adverse events were infusion-related reactions, nausea and headache. Stable disease was observed as best response in 8 of 24 response-evaluable patients.

The pharmacokinetic and CD16A receptor occupancy data demonstrate good target engagement at doses of 320 mg and 480 mg. Pharmacodynamic activity was observed at doses of 160 mg and higher. The recommended phase 2 dose was determined at 480 mg based on safety and tolerability, exposure and CD16A receptor occupancy. The maximum tolerated dose was not reached by the treatment regimen up to 480 mg. Enrollment in the dose escalation has continued at a dose of 720 mg for the purpose of collecting additional data on safety and tolerability.

"Having reached a safe and well-tolerated recommend phase 2 dose with pharmacologic and pharmacodynamic activity is a major milestone for the AFM24 program," said Dr. Andreas Harstrick, Chief Medical Officer at Affimed. "This has been important for the initiation of a broad development program assessing the efficacy of AFM24 as monotherapy and in combinations, and we’re planning to provide first updates on the studies in 2022."

Affimed is enrolling patients in three open label phase 1/2a studies, evaluating the activity of AFM24 as monotherapy (AFM24-101), and in combination with Roche’s anti-PD-L1 checkpoint inhibitor atezolizumab (AFM24-102) as well as in combination with SNK01, NKGen Biotech’s NK cell product (AFM24-103).

The abstract and poster are electronically accessible for participants of the AACR (Free AACR Whitepaper) conference following this link: https://bit.ly/3ukFMqc

An update of another ICE, AFM13, combined with cord blood-derived NK cells in patients with CD30-positive lymphoma will be presented on Sunday, April 10, 1:00 – 3:00 p.m. CST in the session Clinical Trials of Cellular Immunotherapies.

About AFM24
AFM24 is a tetravalent, bispecific innate cell engager (ICE) that activates the innate immune system by binding to CD16A on innate immune cells and EGFR, a protein widely expressed on solid tumors, to kill cancer cells. Generated by Affimed’s fit-for-purpose ROCK platform, AFM24 represents a distinctive mechanism of action that uses EGFR as a docking site to engage innate immune cells for tumor cell killing through antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis.
Affimed is evaluating AFM24 as a monotherapy (AFM24-101) for patients with advanced EGFR-expressing solid malignancies whose disease has progressed after treatment with previous anticancer therapies. The first-in-human Phase 1/2a open-label, non-randomized, multi-center, multiple ascending dose escalation and expansion study and can be found at www.clinicaltrials.gov using the identifier NCT04259450. Furthermore, AFM24 is evaluated in a phase 1/2a study in combination with Roche’s anti-PD-L1 checkpoint inhibitor atezolizumab (AFM24-102, NCT05109442). Affimed and NKGen Biotech have initiated a Phase 1/2a study , investigating AFM24 in combination with SNK01, NKGen Biotech’s NK cell product (AFM24-103, NCT05099549).

On April 8, 2022 Cardiff Oncology, Inc. (Nasdaq: CRDF), a clinical-stage biotechnology company leveraging PLK1 inhibition to develop novel therapies across a range of cancers, reported the results of preclinical studies evaluating the anti-cancer activity of onvansertib in combination with the PARP inhibitor (PARPi) olaparib in PARPi-resistant patient-derived xenograft (PDX) ovarian cancer models (Press release, Cardiff Oncology, APR 8, 2022, View Source [SID1234611729]). The results are featured in a poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, which is taking place both virtually and in-person at the Ernest N. Morial Convention Center in New Orleans, Louisiana from April 8-13, 2022.

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"In these studies, we sought to evaluate how combining onvansertib with PARP inhibition, an approved maintenance treatment for ovarian cancer, might mitigate the known phenomenon of acquired tumor resistance to PARP inhibitors," said Tod Smeal, Ph.D., chief scientific officer at Cardiff Oncology. "We are very pleased with the results, which showed onvansertib and olaparib synergistically combining to generate strong activity against PARPi-resistant patient-derived ovarian cancer models. Given the current lack of effective treatment options for patients showing PARPi resistance, we believe these data are supportive of evaluating this combination within a PARPi-resistant clinical setting."

Preclinical studies featured in the AACR (Free AACR Whitepaper) poster evaluated onvansertib-olaparib combination treatment in three olaparib-resistant patient-derived xenograft (PDX) ovarian cancer models. Two of the three PDX models used (MNHOC22, MNHOC266) were cisplatin-sensitive with a mutated BRCA1 gene, while the third (MNHOC316DDP) was cisplatin-resistant with wild type BRCA1. BRCA1-mutant tumor cells are deficient for homologous recombination (HR)-mediated DNA repair and are initially sensitive to PARPi. This suggests that PARPi resistance was acquired in the MNHOC22 and MNHOC266 tumors due to the restoration of HR-mediated DNA repair, while being naturally conferred in MNHOC316DDP tumors due to continuous HR-proficiency.

Data showed that combining onvansertib with olaparib led to a statistically significant survival benefit compared to treatment with either agent alone in each of the three evaluated PDX models. Results showed the combination was well tolerated.

An electronic copy of the poster and corresponding abstract, entitled, Combining PARP inhibition with the Polo-like kinase 1 (PLK1) inhibitor onvansertib overcomes PARP inhibitor resistance, is available to registered attendees of the AACR (Free AACR Whitepaper) annual meeting on the meeting website. The in-person presentation will take place during the "Drug Resistance and Reversal of Resistance" poster session on April 12, 2022, from 1:30 PM – 5:00 PM CT. Following the meeting, the poster will be available on the "Scientific Presentations" section of the Cardiff Oncology website at View Source

On April 8, 2022 Moleculin Biotech, Inc., (Nasdaq: MBRX) ("Moleculin" or the "Company"), a clinical stage pharmaceutical company with a broad portfolio of drug candidates targeting highly resistant tumors and viruses, reported that preclinical data of Annamycin tested in syngeneic models of metastatic colorectal cancer established in lungs or liver was accepted for poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2022, being held April 8-13, 2022, in New Orleans, Louisiana (Press release, Moleculin, APR 8, 2022, View Source [SID1234611728]).

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Moleculin Biotech, Inc. is a clinical stage pharmaceutical company focused on the development of a broad portfolio of oncology drug candidates for the treatment of highly resistant tumors. (PRNewsfoto/Moleculin Biotech, Inc.)

Details of the poster presentation are as follows:

Title: New approach to target metastatic colorectal cancer organotropism with L-Annamycin
Track: Experimental and Molecular Therapeutics
Poster Number: 4048
Session: PO.ET06.05 – New Chemotherapy Agents
Presentation Type: E-Poster presentation
Session Date and Time: Wednesday, April 13, 2022, from 9:00 am – 12:30 p.m. CDT
Section: 27

The objective of this study was to assess the efficacy of Annamycin in experimental colorectal cancer liver and lung metastasis models. The efficacy of Annamycin was tested in syngeneic models of metastatic colorectal cancer established in lungs or liver. For lung metastasis model, CT26-Luc cells were injected intravenously (IV) into Balb/c mice, followed by weekly IV treatment of Annamycin (4 and 6 mg/kg). The liver metastatic model was established using intrasplenic injection protocol. Mice received six weekly IV injections of 4 mg/kg of Annamycin or vehicle. Bioluminescent imaging (BLI), Magnetic Resonance Imaging (MRI) or Computer Tomography (CT) were used to track tumor progression.

Annamycin exhibited robust antitumor activity in both models. In the lung metastasis model, a dose-dependent delay in the tumor progression was visualized by both BLI and CT scan in the Annamycin treated group. The delay correlated with 272% extension of survival in the group receiving 6 mg/kg Annamycin [median survival (MS) 79d for treated vs 29d vehicle, p<0.0001] and 234% for the animals dosed with Annamycin at 4 mg/kg [MS 68d, p=0.0012]. In the liver metastasis model, all vehicle-treated mice showed massive tumors in the liver and peritoneal cavity as monitored by BLI and MRI. In the vehicle group, 13/14 died or were euthanized by 35d (median survival was 34.5d). Yet, no tumors were detected by BLI or MRI in Annamycin treated mice as of 44d and 0/14 mice died (100% survival). This indicates a highly significant (P< 0.0001) extension of survival (ongoing experiment).

"We continue to be encouraged by the growing body of robust preclinical and human clinical data demonstrated by Annamycin. The positive results seen in these preclinical models provide added confidence in the potential follow-on development opportunities we believe Annamycin holds. While metastatic colorectal cancer is not an immediate area of focus for us, this data set continues to provide valuable insight as we advance its clinical development for the treatment of highly resistant tumors," commented Walter Klemp, Chairman and CEO of Moleculin.

In summary, the strategy to develop anticancer agents that imitate metastatic colorectal cancer organotropism appears to be highly promising and is supported by these results. This study demonstrating efficacy of Annamycin in colorectal cancer models provides convincing evidence for further preclinical development aimed at initiation of clinical studies in metastatic colorectal cancer patients.

Annamycin is the Company’s next-generation anthracycline that has been shown in animal models to accumulate in the lungs at up to 30-fold the level of doxorubicin, as well as demonstrating the ability to avoid the multidrug resistance mechanisms that typically limit the efficacy of doxorubicin and other currently prescribed anthracyclines. Importantly, Annamycin has also demonstrated a lack of cardiotoxicity in multiple human clinical trials, including ongoing trials for the treatment of relapsed or refractory acute myeloid leukemia (AML) and soft tissue sarcoma (STS) lung metastases, and the Company believes that the use of Annamycin may not face the same usage limitations imposed on doxorubicin, one of the most common currently prescribed anthracyclines. Annamycin is currently in development for the treatment of AML and STS lung metastases and the Company believes it may have the potential to treat a number of additional indications.

Annamycin currently has Fast Track Status and Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) for the treatment of STS lung metastases, in addition to Orphan Drug Designation for the treatment of relapsed or refractory acute myeloid leukemia.

For more information about the Phase 1b/2 study evaluating Annamycin for the treatment of STS lung metastases, please visit clinicaltrials.gov and reference identifier NCT04887298.