Patients diagnosed with an advanced-stage cancer present a dismal prognosis due to the presence of metastases. From the primary tumor, the cancer cells are disseminated via lymphatic circulation; metastases develop initially in lymph nodes. Therefore, the targeting of lymph nodes needs to be improved in the design of future chemotherapy, and one way to ensure this targeting is by using the subcutaneous (SC) route. Using lipid nanocapsules (LNCs) (40 nm and fluorescently-labeled with DiD) as nanocarriers, a correlation between the SC injection site (behind the neck, the right and left flanks, and above the tail) for LNC administration and specific lymph node accumulation (left and right cervical, axillary and inguinal lymph nodes) was achieved for Sprague-Dawley rats. The pharmacokinetic and biodistribution profiles confirmed the absence of LNCs in systemic circulation after SC administration due to the optimal size of the LNCs. With appropriate SC administration, LNCs can accumulate in specific lymph nodes, whereas IV administration led to a weak accumulation of LNCs in all lymph nodes. Specific accumulation followed the lymph flow: bottom-up from the lower to upper limbs and top down from the head, with two lymph circulation partitions: right upper limb and the rest. Administration above the tail presented high inguinal and axillary lymph node accumulation whereas weak accumulation was observed after administration behind the neck. LNCs administered in the left flank only accumulated in the left inguinal and axillary lymph nodes, whereas left and right inguinal and axillary lymph nodes presented accumulation after administration in the right flank. Cervical lymph nodes, in the opposite direction of lymph flow, were never targeted after SC administration, whatever the injection site. Keywords: lipid nanocapsules; lymph-node targeting; subcutaneous administrationUsers without a subscription are not able to see the full content. Please, subscribe or login to access all content.
Abstract:Patients diagnosed with an advanced-stage cancer present a dismal prognosis due to the presence of metastases. From the primary tumor, the cancer cells are disseminated via lymphatic circulation; metastases develop initially in lymph nodes. Therefore, the targeting of lymph nodes needs to be improved in the design of future chemotherapy, and one way to ensure this targeting is by using the subcutaneous (SC) route. Using lipid nanocapsules (LNCs) (40 nm and fluorescently-labeled with DiD) as nanocarriers, a correlation between the SC injection site (behind the neck, the right and left flanks, and above the tail) for LNC administration and specific lymph node accumulation (left and right cervical, axillary and inguinal lymph nodes) was achieved for SpragueDawley rats. The pharmacokinetic and biodistribution profiles confirmed the absence of LNCs in systemic circulation after SC administration due to the optimal size of the LNCs. With appropriate SC administration, LNCs can accumulate in specific lymph nodes, whereas IV administration led to a weak accumulation of LNCs in all lymph nodes. Specific accumulation followed the lymph flow: bottom-up from the lower to upper limbs and top down from the head, with two lymph circulation partitions: right upper limb and the rest. Administration above the tail presented high inguinal and axillary lymph node accumulation whereas weak accumulation was observed after administration behind the neck. LNCs administered in the left flank only accumulated in the left inguinal and axillary lymph nodes, whereas left and right inguinal and axillary lymph nodes presented accumulation after administration in the right flank. Cervical lymph nodes, in the opposite direction of lymph flow, were never targeted after SC administration, whatever the injection site.
Fluorescent dyes have been used in medical diagnostics for over 50 years. The emergence of new fluorescent imaging technology in support of surgery and the need for increased sensitivity and precision have driven the search for novel fluorescent molecules. Orthotopic patient-derived pancreatic tumor models provide a closely related human tumor within organ-specific tumor microenvironment, which was well suited to the evaluation of the tissue specificity of two novel fluorescent compounds. To this end, we have developed an orthotopic tumor model of IM-PAN-15 (PDX model developed within the IMODI consortium), a patient derived pancreatic adenocarcinoma, in mice. Tumor cells were amplified subcutaneously in SCID mice and the resulting fragments subsequently surgically implanted into the pancreas of irradiated BALB/c nude mice. Tumor development was monitored in vivo by MRI at three time points. Fluorescent compounds were injected intravenously 36 days after tumor fragment implantation, when mean tumor volumes were approximately 70 mm³. Ex-vivo fluorescent imaging showed that 2h after injection, the two novel fluorescent compounds were present in the pancreas and tumor at roughly equivalent amounts. However, 48h after injection, a clear preferential distribution for the tumor was observed, with both compounds producing an approximately four-fold higher fluorescent signal in the tumor than in the surround pancreatic tissue. This effect persisted six days after injection, although the signal decreased over time. In comparison, indocyanine green, a dye widely used in medical diagnostics, showed no specific accumulation in either the pancreas or tumor. In conclusion, we report the development of a clinically relevant, patient-derived orthotopic tumor model and demonstrate its use in the investigation of tissue specificity of two novel fluorescent compounds. Keywords: PDX, fluorescent dyes, orthotopic pancreatic model, MRI Citation Format: Olivier Duchamp, Cyril Berthet, Peggy Provent, Elodie Marie Dit Chatel, Jordan Longin, Stanislas Urbain, François Scherninski. Development of an orthotopic murine model of a patient-derived pancreatic adenocarcinoma to evaluate the tissue specificity of two novel fluorescent compounds [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1659.
Eighty five percent of preclinical agents entering oncology clinical trials fail to demonstrate sufficient safety or efficacy to gain regulatory approval (1). This failure rate shows a weak understanding of the complexity of human cancer, the continued limitations of the predictive value of existing preclinical models and the scale at which cancer models are interrogated in the preclinical setting (2). Consequently, there is a need of new experimental models that better replicate the diversity of human tumor biology in a preclinical setting. It is now evidenced that PDXs models recapitulate human tumor biology and predict patient drug response (3) by directly comparing drug responses in patients and their corresponding xenografts. To extend such observations to a greater number of human cancers, we have generated in collaboration with EISAI an extensive collection of breast cancer PDXs. Similar to what is observed in the clinic, 60% of our breast PDX panel is classified as estrogen receptor (ER) positive. Tested compounds which interfere with the ER pathway as anti-estrogens (fulvestrant) or estrogen deprivation (without estrogen supplementation, or ovariectomy), are able to decrease the tumor growth in PDX-bearing mice. However, in clinic, endocrine treatment efficacy is limited by intrinsic and acquired resistance (4). The main mechanisms of resistance to these therapies are lack of expression of ER, deregulation of ER-associated transcription factors, coactivators, activation of receptor tyrosine kinase signaling, and aberrant expression of cell-cycle regulators (5). In order to reconcile this need for relevant preclinical models and to study acquired resistance we developed a panel of breast cancer PDX models either resistant to fulvestrant or able to grow in the complete absence of estrogen (ovariectomy or without estrogen supplementation). Each generated tumor was then analyzed by IHC for their ER/PR expression. Whole exome mutation and gene expression were also analyzed and compared to the parental tumor. 1: Arrowsmith, J. & Miller, P. Trial watch: phase II and phase III attrition rates 2011-2012. Nat. Rev. Drug Discov. 12, 569 (2013). 2: Paul, S.M. et al. How to improve R&D productivity: the pharmaceutical industry's grand challenge. Nat. Rev. Drug Discov. 9, 203-214 (2010). 3: Hidalgo, M. et al. Patient-derived xenograft models: an emerging platform for translational cancer research. Cancer Discov. 4, 998-1013 (2014). 4. Ring, A. & Dowsett, M. Mechanisms of tamoxifen resistance. Endocr Relat Cancer 11:643-58 (2004). 5. Hanny, A. & Abdel-Hafiz. Epigenetic mechanisms of tamoxifen resistance in luminal breast cancer. Diseases Jul 6;5(3) (2017). Citation Format: Marc Hillairet de Boisferon, Ismahene Benzaid, Elodie Marie Dit Chatel, Nicolas Hoffmann, Bruce Littlefield. Development of a panel of breast cancer patient-derived xenograft models (PDX) with estrogen independence and/or acquired resistance to endocrine treatment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5281.
Eribulin is a pharmaceutically optimized analog of the marine natural product halichondrin B. As its clinically formulated mesylate salt (Halaven®), eribulin is used for treatment of certain patients with advanced breast cancer and liposarcoma. Mechanistically, eribulin combines cytotoxic tubulin-based antimitotic effects with non-cytotoxic effects on tumor biology, including vascular remodeling, increased perfusion, mitigation of hypoxia and reversal of epithelial to mesenchymal transition (EMT). Reversal of EMT involves cell differentiation pathways that impinge on the G1/S cell cycle boundary. Since estrogenic signaling also impinges on the G1/S boundary, we asked if eribulin could combine advantageously with inhibitors of cyclin dependent kinases and hormonal agents that disrupt estrogenic signaling. Using PDX models of hormone receptor positive (HR+) breast cancer, we previously showed that combining eribulin and palbociclib is considerably more effective than either agent alone, using a “palbociclib holiday” strategy of withholding daily palbociclib doses the day before and the day of weekly eribulin doses to avoid possible cell cycle based antagonism. Here, we ask if the palbociclib holiday is strictly necessary for robust eribulin + palbociclib combination activity, and if triple combinations of eribulin, palbociclib and fulvestrant result in even better anticancer activity than doublet dosing. For the holiday/no holiday comparison, 0.125 mg/kg eribulin was dosed iv Q7Dx3, with palbociclib dosed po either at 150 mg/kg or 107 mg/kg on Q1Dx5[x3 weeks] (holiday) or Q1Dx21 (no holiday) schedules, respectively, resulting in equal palbociclib dose intensities for the 2 schedules. Results showed that synergism was seen in combination with or without palbociclib holiday, but superior results occur with holiday. Using the holiday strategy, we next investigated triple combinations of eribulin, palbociclib and fulvestrant. As single agents at the minimally effective doses selected, eribulin, palbociclib and fulvestrant led to treated/control values (T/C%) of 64%, 63% and 48%, respectively. Combining eribulin and palbociclib led to markedly superior anticancer activity (T/C 23%). Combining eribulin and fulvestrant also led to superior activity (T/C 22%), as did combining fulvestrant and palbociclib (T/C 19%). The triple combination generated the most robust activity at T/C 8%. By mouse RECIST criteria, 10%, 10% and 20% partial responses (PR) were observed for each doublet (fulvestrant/palbociclib, fulvestrant/eribulin, palbociclib/eribulin), respectively. In contrast, 90% PR was seen for the triple combination. These preclinical results support clinical exploration of eribulin, palbociclib and fulvestrant triple combinations for appropriate patients with HR+ breast cancers. Citation Format: Marc Hillairet de Boisferon, Elodie Marie Dit Chatel, Kenichi Nomoto, Bruce A. Littlefield. Synergistic anticancer activity of triple combinations of eribulin, palbociclib and fulvestrant in hormone dependent patient-derived xenograft (PDX) models of human breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4719.
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