Combining the strength of genomics, nanoparticle technology, and direct intraductal delivery for breast cancer treatment

Teo, Wei Wen; Sukumar, Saraswati

doi:10.1186/bcr3656

Cited by 6 publications

(5 citation statements)

References 11 publications

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“…5). Note that breast tumors were observed in non-transgenic mice within a year of exposure to ID chemotherapy or immunoradiotherapy [9, 13, 14, 18].…”

Section: Discussionmentioning

confidence: 99%

“…Independent clinical studies reported a > 88% success rate in ID administration of pegylated liposomal doxorubicin or carboplatin in up to 8 ductal trees per patient [4, 5]. However, there are limitations with these ID approaches for primary prevention in humans: (i) local cytotoxic therapy (e.g., doxorubicin, fluorouracil, and cisplatin) can induce tumors in treated animals [9, 14, 18], a result that has diminished the enthusiasm for its clinical application, and (ii) local hormonal or siRNA-based therapy would require frequent and repeated intraductal injections [10, 16, 17], which makes it impractical for general clinical application.…”

Section: Introductionmentioning

confidence: 99%

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Ductal tree ablation by local delivery of ethanol prevents tumor formation in an aggressive mouse model of breast cancer

et al. 2019

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BackgroundProphylactic mastectomy is the most effective intervention to prevent breast cancer. However, this major surgery has life-changing consequences at the physical, emotional, psychological, and social levels. Therefore, only high-risk individuals consider this aggressive procedure, which completely removes the mammary epithelial cells from which breast cancer arises along with surrounding tissue. Here, we seek to develop a minimally invasive procedure as an alternative to prophylactic mastectomy by intraductal (ID) delivery of a cell-killing solution that locally ablates the mammary epithelial cells before they become malignant.MethodsAfter ID injection of a 70% ethanol-containing solution in FVB/NJ female animals, ex vivo dual stained whole-mount tissue analysis and in vivo X-ray microcomputed tomography imaging were used to visualize ductal tree filling, and histological and multiplex immunohistochemical assays were used to characterize ablative effects and quantitate the number of intact epithelial cells and stroma. After ID injection of 70% ethanol or other solutions in cancer-prone FVB-Tg-C3(1)-TAg female animals, mammary glands were palpated weekly to establish tumor latency and examined after necropsy to record tumor incidence. Statistical difference in median tumor latency and tumor incidence between experimental groups was analyzed by log-rank test and logistic mixed-effects model, respectively.ResultsWe report that ID injection of 70% ethanol effectively ablates the mammary epithelia with limited collateral damage to surrounding stroma and vasculature in the murine ductal tree. ID injection of 70% ethanol into the mammary glands of the C3(1)-TAg multifocal breast cancer model significantly delayed tumor formation (median latency of 150 days in the untreated control group [n = 25] vs. 217 days in the ethanol-treated group [n = 13], p value < 0.0001) and reduced tumor incidence (34% of glands with tumors [85 of 250] in the untreated control group vs. 7.3% of glands with tumor [7 of 95] in the ethanol-treated group, risk ratio = 4.76 [95% CI 1.89 to 11.97, p value < 0.0001]).ConclusionsThis preclinical study demonstrates the feasibility of local ductal tree ablation as a novel strategy for primary prevention of breast cancer. Given the existing clinical uses of ethanol, ethanol-based ablation protocols could be readily implemented in first-in-human clinical trials for high-risk individuals.

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“…5). Note that breast tumors were observed in non-transgenic mice within a year of exposure to ID chemotherapy or immunoradiotherapy [9, 13, 14, 18].…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ductal tree ablation by local delivery of ethanol prevents tumor formation in an aggressive mouse model of breast cancer

et al. 2019

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“…These studies provide strong support for the translational feasibility of ID delivery of cytotoxic or other solutions. Unfortunately, local cytotoxic treatment with pegylated liposomal doxorubicin, 5-fluorouracil, and/or cisplatin can induce tumors with long latency in non-transgenic animals [89,94,146]. This result has diminished enthusiasm for such local chemotherapy delivery unless it is needed to minimize systemic exposure [89,146].…”

Section: Intraductal Chemotherapy and Targeted Treatmentsmentioning

confidence: 99%

“…It would be a one-time treatment in contrast to other ID approaches that require repeated administration of active agents which can be a challenge, especially for chemotherapy agents that may compromise ductal tree structure and leak out of intended targeted area in later cycles. Currently, there are no reports linking clinical uses of EtOH to iatrogenic cancer, but this is a concern for other local treatments that cause DNA damage such as radioimmunotherapy and chemotherapy (Figure 3D,E; refs [94,99,146,171]). The International Agency for Research on Cancer considers EtOH to be carcinogenic to humans [172]; however, this is based on chronic exposure to EtOH as an alcoholic beverage.…”

Section: Ductal Tree Ablationmentioning

confidence: 99%

Systemic and Local Strategies for Primary Prevention of Breast Cancer

Zaluzec,

Sempere

2024

Cancers

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One in eight women will develop breast cancer in the US. For women with moderate (15–20%) to average (12.5%) risk of breast cancer, there are few options available for risk reduction. For high-risk (>20%) women, such as BRCA mutation carriers, primary prevention strategies are limited to evidence-based surgical removal of breasts and/or ovaries and anti-estrogen treatment. Despite their effectiveness in risk reduction, not many high-risk individuals opt for surgical or hormonal interventions due to severe side effects and potentially life-changing outcomes as key deterrents. Thus, better communication about the benefits of existing strategies and the development of new strategies with minimal side effects are needed to offer women adequate risk-reducing interventions. We extensively review and discuss innovative investigational strategies for primary prevention. Most of these investigational strategies are at the pre-clinical stage, but some are already being evaluated in clinical trials and others are expected to lead to first-in-human clinical trials within 5 years. Likely, these strategies would be initially tested in high-risk individuals but may be applicable to lower-risk women, if shown to decrease risk at a similar rate to existing strategies, but with minimal side effects.

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“…Very occasionally, other organs, such as ovaries, uterus, spleen, kidney, and liver, may also develop carcinoma (10), and these drawbacks limit the stability of the model for studying preventive therapies. Intraductal (i.duc) administration of MNU places the agent directly into the mammary ductal system, thus making it possible to induce tumors at predictable locations (11). Direct contact of rat luminal epithelial cells with MNU may also improve the efficiency of carcinogenesis and i.duc delivery can reduce the administration of MNU.…”

Section: Introductionmentioning

confidence: 99%

Intraductal administration of N-methyl-N-nitrosourea as a novel rodent mammary tumor model

et al. 2021

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Background: Chemically induced animal models of breast cancer (BC) using N-methyl-N-nitrosourea (MNU) have been widely used in preclinical research. The conventional approach entails intraperitoneal (i.p) or intravenous injection of a carcinogen, leading to tumor induction at unpredictable locations. This study aimed to establish a modified MNU-induced rat mammary tumor model using intraductal (i.duc) administration and to evaluate its biological behavior, morphology, and response to chemotherapy drugs.Methods: In a pilot experiment, female Sprague-Dawley (SD) rats were injected with either i.duc MNU or vehicle to test the feasibility of this approach. We explored the appropriate dosage for stable tumor formation in pubescent female SD rats by testing a single i.duc dose of MNU (0.5, 1.0 and 2.0 mg) or vehicle.Results: An i.duc injection of 20 μL (1 mg/per duct) MNU in the fourth rat mammary gland induced stable carcinomas in situ. Immunohistochemical (IHC) analysis showed positive expression of estrogen receptor (ER), negative expression of human epidermal growth factor receptor 2 (Her-2), and low expression of Ki-67. Histopathology revealed atypical hyperplasia in the mammary gland 4 weeks after carcinogen injection, developing into carcinoma in situ 5-6 weeks after treatment, with loss of α-SMA and calponin expressions during tumor progression. Albumin-bound paclitaxel (nab-PTX) was injected i.duc and intravenously (i.v) 5 weeks after administration of MNU. The tumor growth rate of the nab-PTX i.duc-treated group was lower than in the i.v and control groups. The number of TUNEL-positive apoptotic cells was significantly higher in the nab-PTX i.duc-treated group.Conclusions: Using i.duc MNU (20 μL, 1 mg) to establish a rat mammary tumor model resulted in a predictable location in the rat mammary gland and exhibited better consistency; i.duc administration of nab-PTX permitted a smaller drug dose, but produced a better drug response, than i.v injection.

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Combining the strength of genomics, nanoparticle technology, and direct intraductal delivery for breast cancer treatment

Cited by 6 publications

References 11 publications

Ductal tree ablation by local delivery of ethanol prevents tumor formation in an aggressive mouse model of breast cancer

Ductal tree ablation by local delivery of ethanol prevents tumor formation in an aggressive mouse model of breast cancer

Systemic and Local Strategies for Primary Prevention of Breast Cancer

Intraductal administration of N-methyl-N-nitrosourea as a novel rodent mammary tumor model

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