CD44

Scientists develop a colorectal cancer cell-activated nanoconjugate-in-alginate drug delivery system for precise, localized antitumor effects BUSAN, South Korea, Feb. 19, 2025 /PRNewswire/ -- Colorectal cancer (CRC) is one of the most prevalent types of cancer and has a high mortality rate globally. Oral administration of anticancer drugs that pass through the gastrointestinal (GI) tract into the colorectum is a common strategy to deliver drugs in CRC treatment. However, this approach presents distinct challenges: most of these drugs lack target-specificity, leading to off-target side effects; these drugs get easily adsorbed onto the microvilli structure of the small intestinal epithelium, resulting in premature drug loss; and systemic drug absorption reduces CRC-targeted drug delivery. These challenges result in insufficient drug accumulation in the tumor cells and reduce the therapeutic efficiency of CRC treatment. Therefore, an innovative drug delivery strategy is urgently needed to ensure localized, precise CRC therapy. Continue Reading Researchers from Pusan National University develop a new strategy for selective local therapy against colorectal cancer. They used a pH-sensitive alginate matrix to shield the drug from exposure to gastric juices. Alginate undergoes a sol-gel-sol transition enabling the release of drugs only at the colorectum, limiting drug loss, ensuring precise drug delivery, and enhancing the therapeutic efficiency of colorectal cancer treatment. To address these challenges, a team of researchers led by Prof. Jin-Wook Yoo from Pusan National University, Republic of Korea, developed a unique drug delivery strategy for CRC therapy. In their exciting work, they proposed a drug delivery strategy by enclosing CRC cell-activated nanoconjugates (CTNCs) inside an alginate (Alg) matrix for highly specific and localized drug release. Prof. Yoo explains, "The main aim of this study is to develop CTNCs-in-alginate (Alg/ CTNCs) by synthesizing a hyaluronic acid (HA)-Poly (D, L-lactide-co-glycolide) (PLGA)-irinotecan (IRI) copolymer (HPI), followed by self-assembly for nanoconjugate formation and incorporation into an alginate matrix for highly CRC-specific oral drug delivery that bypasses the systemic circulation". This paper was made available online on 3rd January 2025 and to be published in Volume 505 of the Chemical Engineering Journal on 1st February 2025. The alginate matrix transitions from a solution-like form to a gel-like form when exposed to the harsh acidic environment of the stomach and intestine, and shields the nanoconjugates, thus suppressing premature drug loss. Upon exposure to the basic pH in the colorectum, it converts back to the solution-like form, and deshields the nanoconjugates, thus delivering the CTNCs to the target tumor cells. The deshielded CTNCs readily interact with the CD44 receptor on the tumor cells via the HA ligand of CTNCs. Once the CTNCs are selectively internalized by CRC cells, the intracellular esterase of the tumor cells cleaves irinotecan from the HPI copolymer, ensuring highly target-specific drug release in vitro and in vivo. Prof. Yoo further explains their results, "The sol-gel transition in the stomach aids in shielding the CTNCs from unwanted interactions with the small intestine epithelium, resulting in facilitated passage and minimized IRI loss before reaching the colorectum. Additionally, completely deshielded CTNCs can be selectively internalized by CRC cells, followed by cancer esterase-triggered drug release within CRC cells, resulting in potent local anticancer effects without systemic side effects". This study presents the successful development of a potential orally administrable drug delivery system that can bypass systemic circulation and precisely target CRC by leveraging the sol-gel-sol transition of alginate in the GI tract. "These findings highlight the potential of reversible shielding/deshielding and target cell-activated drug releasing strategies for the highly selective oral delivery of various therapeutics, such as small molecules, antibodies, and nucleic acid-based drugs, to disease sites in the colorectum", Prof. Yoo adds. The proposed drug delivery strategy can also be extended to treat other colorectum-specific diseases, such as ulcerative colitis. Reference Title of original paper: On-site sol-gel-sol transition of alginate enables reversible shielding/ deshielding of tumor cell-activated nanoconjugates for precise local colorectal cancer therapy Journal: Chemical Engineering Journal DOI: About Pusan National University Website: Contact: Goon-Soo Kim 82 51 510 7928 [email protected] SOURCE Pusan National University WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

THURSDAY, Aug. 22, 2024 -- Elevated salivary levels of CD44 and total protein (TP) can identify head and neck cancer patients with an increased risk for cancer recurrence, according to a study published online Aug. 15 in JAMA Otolaryngology-Head and Neck Surgery . Elizabeth J. Franzmann, M.D., from the University of Miami Health System and Jackson Memorial Hospital, and colleagues conducted a multi-institutional nonrandomized clinical trial testing a novel diagnostic/screening assay to examine whether soluble CD44 and TP are useful for monitoring head and neck cancer recurrence in a point-of-care (POC) test. Oral rinses were collected at pretreatment baseline and at three, six, 12, and 18 months after completion of therapy. To define disease status, participants were followed for three years. Among the 172 patients who were enrolled, the researchers found an association for tumor site with test results at baseline; a higher baseline positive POC test rate was seen for patients with oral cavity cancer versus oropharyngeal cancer (92.2 versus 77.3 percent). A higher CD44 level showed a significant association with a higher risk for recurrence using Cox regression models with CD44 or TP level as a time-varying covariate (hazard ratio, 1.06). Higher CD44 and TP levels were associated with increased hazard ratios of recurrence of 1.13 and 3.51, respectively, in a multivariate adjusted analysis. “Our study suggests biomarker detection in saliva collected from an oral rinse after initial treatment offers potential to readily assess recurrence risk,” Franzmann said in a statement. “Elevated levels of either of two biomarkers were associated with disease return.” One author disclosed ties to the biopharmaceutical industry and is inventor of the intellectual property used in the study.

Recently, Merus announced that the first patient has been dosed in the phase 3 clinical trial LiGeR-HN2, aimed at evaluating the efficacy of petosemtamab in the second-line and third-line treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (r/m HNSCC). LiGeR-HN2 is a randomized, open-label phase 3 clinical trial primarily assessing the safety and efficacy of petosemtamab compared to standard therapy in patients with recurrent or metastatic head and neck squamous cell carcinoma. The trial will enroll patients who have previously received first-line treatment and whose disease has progressed. The primary endpoints of the study typically include objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety assessments. Petosemtamab is a bispecific antibody developed by Merus that simultaneously targets both the epidermal growth factor receptor (EGFR) and LGR5 (Leucine-rich repeat-containing G protein-coupled receptor 5), receptors which are overexpressed in various types of cancer. By targeting these two receptors, petosemtamab aims to more effectively target and kill cancer cells while reducing the impact on healthy cells. Data presented by Merus at the 2024 American Society of Clinical Oncology (ASCO) showed that in patients with head and neck squamous cell carcinoma (HNSCC), when used in combination with Keytruda, six out of ten evaluable patients demonstrated a tumor response, achieving a response rate of 60%. Furthermore, Merus' latest public materials on their website also released mid-stage clinical updates of petosemtamab as a monotherapy for second-line and beyond HNSCC, which showed a response rate of 37% in 43 evaluable patients (2L+ HNSCC, ORR 37%), and mid-stage clinical updates of its combination with the PD-1 monoclonal antibody Keytruda for first-line HNSCC, which achieved a response rate of 67% in 24 evaluable patients (1L HNSCC, RR 67%). The company projects that by 2028, the global market size for HNSCC will exceed $5 billion, highlighting the substantial commercial potential of petosemtamab for this indication. The FDA has granted petosemtamab Breakthrough Therapy Designation (BTD) for the treatment of patients with recurrent or metastatic HNSCC who have experienced disease progression following platinum-based chemotherapy and anti-programmed cell death receptor-1 (PD-1) or anti-programmed death-ligand 1 (PD-L1) antibody therapy. Partnering with GileadIn early 2024, Gilead Sciences announced that it will pay Merus a $56 million upfront payment and make a $25 million equity investment in the biotech company. Through the partnership with Merus, Gilead Sciences aims to leverage Merus's expertise in the development of bispecific and multispecific antibodies to create innovative antibody therapies. The specific targets of the collaboration have not been disclosed. About LGR5LGR5, also known as GPR49, is a seven-transmembrane protein that belongs to the GPCR superfamily. Within this GPCR superfamily, LGR5, along with LGR4 and LGR6 which are part of the glycoprotein-receptor orphan subgroup, share a distinctive structural feature: a large extracellular domain containing 17 leucine-rich repeat sequences. When LGR5 binds to its ligand R-Spondin (RSPO), it collaborates with the Wnt receptors (Frizzled and LRP5/6) to enhance the Wnt/β-catenin signaling pathway. LGR5 regulates the Wnt/β-catenin signaling pathway in normal intestinal stem cells. For instance, during normal homeostasis of the intestine, the expression of LGR5 is restricted to the stem cell compartments located at the base of the crypts. As the progeny of the stem cells migrate upward through the proliferative zone and undergo differentiation, this expression of LGR5 is lost. Consistently, isolated single LGR5+ cells from the intestine can form self-organizing crypt/villus structures known as organoids, capable of reconstituting all differentiated epithelial lineages present in the intestine. The table below presents the pipeline status of clinical studies related to LGR5, all of which are for cancer-related indications. Merus clearly holds a leading position in this target competition. Next Indication: Colorectal CancerIn an interview with the CEO of Merus, it was also mentioned that the company is looking forward to evaluating petosemtamab in metastatic colorectal cancer (mCRC), which represents another significant potential opportunity. Colorectal cancer (CRC) is the third most commonly diagnosed malignancy worldwide and the fourth leading cause of cancer-related deaths, with its burden expected to increase by 60% by 2030. Despite significant improvements in detection and treatment protocols, most advanced-stage cancer patients will die from recurrence of their disease. A widely recognized reason for CRC recurrence is the failure of existing therapies to eradicate subpopulations of cancer stem cells (CSCs) within the tumor. CSCs express a variety of markers, including CD133, CD44, CD166, ALDH, EphB2, and Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5). These CSCs are capable of resisting therapeutic assaults and re-establishing tumor growth after treatment interventions, creating an urgent need for innovative, non-toxic targeted cancer therapies to induce sustained clinical remission. A key early event in the progression of colorectal cancer is the dysregulation of the Wnt/β-catenin signaling pathway, which is often constitutively activated by genetic mutations in APC or β-catenin. Under normal conditions, the lack of Wnt ligands leads to the constitutive phosphorylation of β-catenin, followed by proteasomal degradation, keeping Wnt target genes suppressed. When Wnt ligands bind to the Wnt receptors Frizzled and LRP5/6, the accumulation of β-catenin in the cytoplasm leads to its nuclear translocation, where it binds with the TCF/LEF family of transcription factors and activates oncogenic Wnt target genes such as c-myc, cyclinD1, and survivin. How to obtain the latest research advancements in the field of biopharmaceuticals? 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