tbuckley/cabot-search huggingface dataset:
Localization of Intramuscular mRNA Delivery using Deep Eutectic‐Lipid Nanocomposites
Authors: Alexander Michael Curreri, Michael Dunne, Michael Griffith Bibbey, Neha Kapate, Jayoung Kim, Samir Mitragotri
Journal: Advanced Healthcare Materials (2024)

Abstract Messenger ribonucleic acid (mRNA) has long been touted as a next‐generation therapeutic modality for infectious disease, cancer, and genetic disorders. Lipid nanoparticles (LNPs) provide an elegant delivery strategy for mRNA cargo to help realize this potential for vaccination. However, systemic exposure seen with traditional LNP formulations can have significant implications on efficacy and safety. Efforts to mitigate this have largely been focused on laborious lipid or LNP redesign. Here, the use of a deep eutectic‐lipid nanocomposite delivery system for the tuning of mRNA expression for intramuscular injections in vivo is reported. One deep eutectic, cholinium malonate, allows for the linear control of percent expression at the muscular injection site based solely on its concentration in the formulation. The same deep eutectic solvent (DES) can increase local muscle expression by 68% and significantly decrease off‐target liver expression by 72%. Physico‐chemical studies suggest that the DES incorporates into or onto the pre‐formed LNPs thus impacting endosomal escape and in situ interactions. These nanocomposites provide new possibilities for previously approved LNP formulations and without the need for lipid redesign to induce localized expression.
Abstract PO3-22-05: Investigating HER2-low tumors from a locoregional perspective- a secondary analysis of a randomized radiotherapy trial
Authors: Per Karlsson, Anikó Kovács, Fredrika Killander, Emma Niméus, Erik Holmberg, Axel Stenmark Tullberg
Journal: Cancer Research (2024)

Abstract Background: With the introduction of antibody-drug conjugates directed against HER2, a new subgroup of tumors with low HER2 expression (1+ or 2+ without amplification) has emerged. HER2 signaling has been implicated in radioresistance in mechanistic studies and is an accepted biomarker of immunogenicity. The study aimed to contrast tumors with low HER2 expression versus zero HER2 expression from a prognostic and radiotherapy-predictive locoregional perspective. Methods: HER2 status was evaluated using immunohistochemistry and SISH in the randomized radiotherapy (RT) cohort, SweBCG91RT, by a board-certified pathologist. HER2-low status was defined as HER2 IHC 1+ or 2+ without amplification, HER2-zero as 0, and HER2-high as HER2 IHC 3+ or SISH amplified. Tumor-infiltrating lymphocytes were assessed on whole-tissue sections and categorized as low (&amp;lt; 10%) or high (≥ 10%). The endpoint was time to ipsilateral breast tumor recurrence (IBTR) as first event. Results: Out of 964 evaluated primary tumors, 433 (44.9%) were classified as HER2-low, 467 (48.4%) as HER2-zero and 64 (6.6%) as HER2-high. TILs levels did not differ between HER2-low and HER2-zero tumors (p=0.33). The hazard ratio for high TILs was 0.79 in HER2-zero tumor (CI 95% 0.43-1.45, p=0.44) and 0.96 in HER2-low tumor (CI 95% 0.56-1.66, p=0.90), and no interaction effect from TILs was observed (p=0.63). The benefit from RT was similar among HER2-low (HR 0.42, CI 95% 0.25-0.72, p=0.001) and HER2-zero tumors (HR 0.31, CI 95% 0.17-0.56, p&amp;lt; 0.001). Conclusions: HER2-low tumors do not differ from HER2-zero tumors regarding the benefit from postoperative RT. Unlike high HER2 expression, low expression is not associated with TILs infiltration. HER2-low tumors likely do not represent a biologically distinct subtype from a locoregional aspect. Citation Format: Per Karlsson, Anikó Kovács, Fredrika Killander, Emma Niméus, Erik Holmberg, Axel Stenmark Tullberg. Investigating HER2-low tumors from a locoregional perspective- a secondary analysis of a randomized radiotherapy trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-22-05.
Abstract PO2-18-12: Updated Results of a Phase II Study: Neoadjuvant Inetetamab Combined with Pertuzumab, Paclitaxel and Carboplatin for Locally Advanced HER2-Positive Breast Cancer
Authors: Yue Chai, Jiaxuan Liu, Mingxia Jiang, Maiyue He, Xin Wang, Yipeng Wang, Xue Yang, Jing Wang, Binghe Xu, Qiao Li
Journal: Cancer Research (2024)

Abstract Background: Inetetamab is a neotype HER2-targeted monoclonal antibody with amino acids modified Fc segment which optimizes the antibody-dependent cellular cytotoxicity effect. However, robust evidence evaluating the combination of inetetamab combined with pertuzumab, paclitaxel and carboplatin (TCbIP) for neoadjuvant therapy is still lacking. This study aimed to evaluate the efficacy and safety of TCbIP as a neoadjuvant therapy for patients with locally advanced HER2-positive breast cancer. We now present the updated results of this trial. Methods: This phase II trial included female patients with histologically confirmed stage IIA to IIIC HER2-positive primary invasive breast cancer. Eligible patients received TCbIP treatment every three weeks for a maximum of six cycles followed by surgery. The primary endpoint was pathologic complete response (pCR, ypT0/is ypN0) rate. Key secondary endpoints included near pCR (npCR, residual breast disease &amp;lt; 1cm) rate, objective response rate (ORR) and safety. Results: From November 2021 to July 2023, 40 patients were enrolled in the trial. One patient received one cycle of the study treatment but was lost to follow-up without surgery, and five patients received one cycle of the study treatment and were still undergoing treatment, leaving 34 patients in the intention-to-treat (ITT) population. Among these 34 patients (82.4% in stage III), 22 patients completed the study treatment and surgery (per-protocol [PP] population) and 12 patients were still undergoing neoadjuvant treatment. The ORR was 91.2% (31/34) in the ITT population and 86.4% (19/22) in the PP population. Among the 22 patients in the PP population, 12 patients (54.5%) achieved pCR, and18 patients (81.8%) achieved npCR. The pCR rates for patients with hormone receptor (HR) negative and positive tumors were 80.0% (8/10) and 33.3% (4/12), respectively. The most common grade 3 adverse event was neutropenia (17.6%). No significant reduction in the left ventricular ejection fraction was observed in any patient. Conclusions: Neoadjuvant therapy with TCbIP demonstrated promising efficacy and manageable toxicity in patients with HER2-positive locally advanced breast cancer. Registration number: NCT05749016 (www.clinicaltrials.gov). Citation Format: Yue Chai, Jiaxuan Liu, Mingxia Jiang, Maiyue He, Xin Wang, Yipeng Wang, Xue Yang, Jing Wang, Binghe Xu, Qiao Li. Updated Results of a Phase II Study: Neoadjuvant Inetetamab Combined with Pertuzumab, Paclitaxel and Carboplatin for Locally Advanced HER2-Positive Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-18-12.
Abstract PO3-27-10: Financial Stress and Care Disruption in Breast Cancer: A Ten-Year National Health Interview Survey Analysis
Authors: Maya Doyle, Erina Quinn, Sarah Bell, Braelyn Wekwerth, Ruth Carlos
Journal: Cancer Research (2024)

Abstract Background: Financial stress is an adverse event of BC. Increased availability of oral targeted therapy (OTT) is hypothesized to add to this burden. We assess financial stress at the population level as a function of availability of OTT. Design: We used 2013-2022 NHIS adult BC population data. Financial stress markers were care disruption, food insecurity and percent home ownership. Care disruption was defined as at least 1 event of skipping or taking less medication or delayed filling or unable to afford prescriptions. Available oral therapy Florida Blue July 2023 was cross-referenced with the NCI targeted therapy list for breast cancer as of July 2023. Initial FDA approval date for breast cancer for OTT determined the number of available OTT by survey year. We conducted a time-adjusted logistic regression to account of external effects such as COVID and adjusted for sociodemographics. Results: In a population of over 30 million respondents with BC, care disruption affected &amp;lt; 10%; food insecurity, &amp;lt; 1.3%, &amp;gt;83% reported home ownership. The number of available OTT did not affect outcomes. Survey year was associated with reduced care disruption (adjusted OR 0.82, 95% CI 0.68–0.99). Self-reported Black race affected home ownership (aOR 0.57, 95% CI 0.43-0.77) and any care disruption (a2.11, 95% CI 1.38-3.24). Non-White patients more likely reported food insecurity (aOR 5.56, 95% CI 2.58-12.01). Income &amp;lt; 200% of poverty level negatively affected outcomes. Stroke (aOR 1.97, 95% CI 1.09-3.55) and heart attack (aOR 2.10, 95% CI 1.11–4) history increased likelihood of care disruption. Conclusion: Available number of OTT did not influence financial stress in a BC population. Adverse sociodemographics and comorbidities correlated with care disruption. Our study was limited by absence of actual OTT use; further assessment at the individual level is needed. Table. Outcomes Citation Format: Maya Doyle, Erina Quinn, Sarah Bell, Braelyn Wekwerth, Ruth Carlos. Financial Stress and Care Disruption in Breast Cancer: A Ten-Year National Health Interview Survey Analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-27-10.
Abstract PO3-04-09: Prognoses of Patients with Hormone Receptor-Positive andHuman Epidermal Growth Factor Receptor 2-Negative BreastCancer Receiving Neoadjuvant Chemotherapy before Surgery:A Retrospective Analysis
Authors: Jin Zhang, Yan Liu, Shichao Zhang
Journal: Cancer Research (2024)

Abstract Abstract: Purpose: To evaluate the clinical characteristics, pathological response, and prognostic significance of hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2−) breast cancer (BC) after neoadjuvant chemotherapy (NAC). Methods: A survival analysis was performed to detect the factors related to recurrence and death in 3070 consecutive patients with HR+/HER2− BC who received NAC from 2011 to 2022. All patients received current “standard of care” following neoadjuvant therapy based on guidelines, including surgery and adjuvant endocrine therapy. HER2-low was defined as immunohistochemistry (IHC) 1+ or IHC 2+ and fluorescence in-situ hybridization-negative. Results: The complete pathological response (pCR) (ypT0/is ypN0) rate was 14.5%. The clinical tumor size (cT), ER scores, PR status, and Ki67 levels were related to pCR. The 5-year disease-free survival (DFS) and overall survival (OS) rates were 82.6% and 90.4%, respectively. PR, Ki67 levels, and postmastectomy radiotherapy were independent factors for DFS and OS, and the extranodal extension (ENE) correlated with DFS. However, pCR and HER2 status were related to OS. The pCR rate in PR negativity BC was significantly higher than that in PR positivity BC (21.1% vs. 12.2%, p = 0.000), but PR negativity BC had a poorer prognosis than PR positivity BC. HER2-low BC showed high ER scores (over 50%), PR positivity, large ypT, ENE, and lymphovascular invasion but a lower pCR rate than HER2-zero BC. Patients with HER2-low BC had shorter OS than those with HER2-zero BC (p = 0.037). However, there was no difference in DFS. Conclusions: Depending on PR status and HER2 status, patients with ER positivity and HER2 negativity exhibit different pathologic complete response rates to neoadjuvant chemotherapy and long-term outcomes, especially patients with PR negativity or HER2-low status. Keywords: breast cancer; neoadjuvant chemotherapy; survival; prognosis; PR; HER2-low Citation Format: Jin Zhang, Yan Liu, Shichao Zhang. Prognoses of Patients with Hormone Receptor-Positive andHuman Epidermal Growth Factor Receptor 2-Negative BreastCancer Receiving Neoadjuvant Chemotherapy before Surgery:A Retrospective Analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-04-09.
Abstract PO4-03-12: De-escalating treatment with neoadjuvant chemotherapy in early triple-negative breast cancer
Authors: Serafin Morales Murillo, Ariadna Gasol Cudós, Noemí Tuset Der-Abrain
Journal: Cancer Research (2024)

Abstract Neoadjuvant chemotherapy (NAT) is a standard treatment in early triple-negative breast cancer, but the regimen and duration of this treatment are controversial. We analyze a cohort of early triple negative breast cancer treated with NAT with different schemas to determine its efficacy. 272 patients treated with NAT since 2001 to 2020 were selected. The median age of the group was 57 years (27-85), initial size 30 mm (9-122) and Ki67 expression was 60 (7-100). 107 patients (39.3%) had histologically confirmed initial axillary involvement and the regimens of chemotherapy used were carboplatin AUC 5 + weekly paclitaxel (80 mg/m2) x 4 cycles in 56 cases (21%) (SCHEME A), same scheme followed by 4 cycles of adriamycin 50 mg/m2 + cyclophosphamide 500 mg/m2 in 85 cases (31%) (SCHEME B), Adriamycin 50 mg/m2 + cyclophosphamide 500 mg/m2 × 4 cicles in 44 (16%) (SCHEME C) and Adriamycin 50 mg/m2 + cyclophosphamide 500 mg/m2 × 4 cicles followed by docetaxel 100 mg/m2 × 4 cicles in 87 (32%) (SCHEME D). We achieved a 51% of pathologic complete response (pCR),and a total of 24% of recurrences. The proportion of PCR and recurrence according to the different schemes is represented in the following table. The clinical factors associated with recurrence were the initial size (OR 8.6), the initial axillary involvement (OR 4.21) and the absence of pCR (OR 8.14), and for patients with pCR it was only the initial axillary involvement (OR 3.4). Patients that received schema A in NAT only presented a total of 5% of recurrence (3/56), only in patients with initial axillary involvement. The NAT schema with carboplatin AUC 5 + weekly paclitaxel (80 mg/m2) x 4 cycles is safe in patients without initial nodal involvement with high pathologic complete response (62%) and lower recurrence rate (9% in nonPCR and 3% in pCR). Therefore, it could be considered as a standard scheme of neoadjuvant chemotherapy for patients without axillary involvement. Table. SCHEMA A (20%) B (31%) C (16%) D (32%) Pcr 62% 63% 41% 37% Recurrence in pCR 3% 7% 16% 9% Recurrence in nonpCR 9% 16% 50% 63% Citation Format: Serafin Morales Murillo, Ariadna Gasol Cudós, Noemí Tuset Der-Abrain. De-escalating treatment with neoadjuvant chemotherapy in early triple-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-03-12.
Abstract PO3-28-05: Therapeutic Plasmapheresis as a Symptomatic Treatment for Paclitaxel-Associated Peripheral Polyneuropathy
Authors: Sardor Abdugafforov, Vladimir Vorotnikov, Alexander Soynov, Tornike Mchedlidze, Igor Kopytich, Sofia Kim
Journal: Cancer Research (2024)

Abstract Relevance: Paclitaxel-associated peripheral polyneuropathy (PIPN) is one of the most common side effects that develop during treatment with drugs of the taxane group. In the treatment of early breast cancer with paclitaxel 80 mg/m2 weekly, 12 injections, PINP develops in 90% of patients of varying severity. The main symptoms are pain and numbness in the arms and legs, which is associated with the accumulation of paclitaxel in the ganglia of the spinal cord, as well as increased expression in the ganglia of the spinal cord of chemokines and cytokines, such as IL-1β, IL-8 and TNF-α, as well as CXCR4, RAGE, CXCL1, CXCL12, CX3CL1 and C3. We hypothesized that the severity of PIPN symptoms can be reduced by lowering the concentration of chemokines and cytokines in the blood by performing plasmapheresis sessions. Research methods: An open prospective study was carried out, the protocol of which was approved by the ethical committee. The study included 30 patients (100% women) aged 30 to 60 years (mean age 45 years) who developed PIPN during paclitaxel therapy 80 mg/m2, weekly, 12 injections. The severity of PIPN symptoms was assessed using a “visual analogue scale” (VAS). The results of the VAS evaluation varied from 6 to 8 points. Patients underwent 5 courses of membrane plasmapheresis with exfusion of 400-500 ml of plasma per session (20 ml per 1 kg of body weight), plasma loss was compensated with saline. Repeated procedures were performed once every two months for 6 months. Results: 30 patients underwent 15 procedures of therapeutic plasmapheresis within 6 months. In 21 patients (70%) there was a pronounced decrease in PIPN symptoms (VAS - 2-3 points), in 3 patients (10%) a moderate decrease in symptoms (VAS -5-6 points), in 6 (20%) no effect of plasmapheresis (VAS - 7-8 points). Approximately 15% of procedures were associated with adverse events, the most common of which were vasovagal reactions; 20% of patients had at least one adverse event. Conclusions: Given the subjective reduction in the severity of PIPN symptoms during courses of therapeutic plasmapheresis in more than 70% of cases, therapeutic plasmapheresis can be used as a symptomatic therapy for PIPN, however, taking into account the subjective assessment of the results by patients, there may be a risk of developing cognitive errors. Therefore, this method of therapy requires more thorough study. Citation Format: Sardor Abdugafforov, Vladimir Vorotnikov, Alexander Soynov, Tornike Mchedlidze, Igor Kopytich, Sofia Kim. Therapeutic Plasmapheresis as a Symptomatic Treatment for Paclitaxel-Associated Peripheral Polyneuropathy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-28-05.
Abstract PO3-28-12: Targeting the KCa3.1 potassium channel arrests ER+ breast cancer growth and re-sensitizes to drug resistance
Authors: Davide Delisi, Metin Cetin, Ozge Saatci, Ozgur Sahin, Saverio Gentile
Journal: Cancer Research (2024)

Abstract Standard of care for breast cancer (BC) treatment including Selective-Estrogen Receptor (ER)-modulators and/or degraders (SERM; tamoxifen, SERD;Fulvestrant) or cyclin-dependent kinases CDK4 and CDK6 (palbociclib) can be effective therapeutic strategies. However, drug toxicity and/or drug resistance severely limit these approaches and patients succumb to the disease. Therefore, there is an urge to develop new therapeutic strategies against ER+-BC. Ion channels are general pharmacological targets however, little is known about the role of this class of proteins in cancer biology. We discovered that expression of the KCa3.1 potassium ion channel is downregulated in ER+-BC. Also, patients expressing high level of KCa3.1 present a better overall survival (OS) and relapse free survival when compared with patients with low expression. Thus, these data indicate that KCa3.1 is a prognostic factor in ER+-BC and that high activity of this channel plays a fundamental role in an oncosuppressor signature. Our central hypothesis is that pharmacological targeting KCa3.1 with activator molecules arrests growth of ER+-BC. We discovered that ER+-BC patient-derived organoids (PDO) and cell lines treated with KCa3.1 agonists including the FDA approved Chlorzoxazone, (CZX) arrests significantly inhibit tumor growth. Activation of KCa3.1 arrested the cell cycle in the G0/G1 phase by activating a senescent-like phenotype. Furthermore, our studies on the biochemical signaling that underlines this event demonstrated that increased expression level of KCa3.1 protein associated with lower expression level of ERa in a cell cycle phase-dependent manner. Furthermore, use of KCa3.1activator produced a proteasomal-dependent ERa degradation. To better characterize the therapeutic benefit of targeting the KCa3.1, we assessed the effects of CZX on developed several tamoxifen and/or palbociclib resistant cell lines and PDO models. We found that the combination of CZX strongly potentiated the lethal effects of both tamoxifen and palbociclib in the relative resistant models. We conclude that pharmacological targeting KCa3.1 potassium channel in ER+-BC can be considered a novel, safe and efficacious therapeutic strategy. Citation Format: Davide Delisi, Metin Cetin, Ozge Saatci, Ozgur Sahin, Saverio Gentile. Targeting the KCa3.1 potassium channel arrests ER+ breast cancer growth and re-sensitizes to drug resistance [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-28-12.
Abstract PO3-28-11: Potassium channel activity unveils breast cancer vulnerability
Authors: Saverio Gentile
Journal: Cancer Research (2024)

Abstract Decades of studies on ion channels have vastly demonstrated the critical functions of these proteins in many physiological and pathological conditions and have provided for an extraordinary pharmacopeia of useful compounds, often with selective actions and minimal side effects. Nevertheless, the function of ion channels in controlling cancer biology is still unknown and underexplored. Our research demonstrates that breast cancer downregulates expression of specific potassium channels (e.g., Kv11.1, KCa3.1) independently of their molecular characterization (ER+, HERB2+ and TNBC). Furthermore, breast cancer patients expressing high protein level of each of these channels presents a better overall survival when compared with patients with low expression. These data indicate that potassium channels can be prognostic factors and that high activity of these protein affects tumor growth. Therefor we wanted to understand the therapeutic benefits of pharmacological targeting specific potassium channels in breast cancer. We discovered that stimulation of the Kv11.1 with specific and selective activator molecules produced a significant growth arrest in a variety of experimental systems including in vitro, in vivo and ex vivo (e.g. Patient-derived organoids) systems. Studying the biochemical pathways that underline these events we discovered that Kv11.1 agonists affects different hallmarks of cancer including metabolism, growth and metastasis signaling without producing significant side effects. For example, use of Kv11.1 agonists produced a strong suppression of oncogene protein function including c-Myc while increasing oncosuppressors such as p21 and p16. These events associated with activation of a senescent phenotype. Furthermore, stimulation of Kv11.1 channel reversed the epithelial-to-mesenchymal transition by inhibiting the WNT signaling and reduced spreading of a TNBC by arresting the metastatic process.. Furthermore, Kv11.1 activation produced a Ca2+-dependent mitochondria damage where the antioxidant transcription factor NRF2 played a fundamental role in determining resistance to death. Therefore, we conclude that targeting the Kv11.1 potassium channel in breasts cancer can be considered a new, effective and safe targeting strategy for breast cancer. Citation Format: Saverio Gentile. Potassium channel activity unveils breast cancer vulnerability [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-28-11.