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Blanco E.,Houston Methodist Research Institute | Sangai T.,The Surgical Center | Wu S.,Houston Methodist Research Institute | Hsiao A.,Houston Methodist Research Institute | And 14 more authors.
Molecular Therapy | Year: 2014

Ongoing clinical trials target the aberrant PI3K/Akt/mammalian target of rapamycin (mTOR) pathway in breast cancer through administration of rapamycin, an allosteric mTOR inhibitor, in combination with paclitaxel. However, synergy may not be fully exploited clinically because of distinct pharmacokinetic parameters of drugs. This study explores the synergistic potential of site-specific, colocalized delivery of rapamycin and paclitaxel through nanoparticle incorporation. Nanoparticle drug loading was accurately controlled, and synergistic drug ratios established in vitro. Precise drug ratios were maintained in tumors 48 hours after nanoparticle administration to mice, at levels twofold greater than liver and spleen, yielding superior antitumor activity compared to controls. Simultaneous and preferential in vivo delivery of rapamycin and paclitaxel to tumors yielded mechanistic insights into synergy involving suppression of feedback loop Akt phosphorylation and its downstream targets. Findings demonstrate that a same time, same place, and specific amount approach to combination chemotherapy by means of nanoparticle delivery has the potential to successfully translate in vitro synergistic findings in vivo. Predictive in vitro models can be used to determine optimum drug ratios for antitumor efficacy, while nanoparticle delivery of combination chemotherapies in preclinical animal models may lead to enhanced understanding of mechanisms of synergy, ultimately opening several avenues for personalized therapy. © The American Society of Gene & Cell Therapy.


A team of investigators from Houston Methodist Research Institute may have transformed the treatment of metastatic triple negative breast cancer by creating the first drug to successfully eliminate lung metastases in mice. This landmark study appears this week in Nature Biotechnology. The majority of cancer deaths are due to metastases to the lung and liver, yet there is no cure. Existing cancer drugs provide limited benefit due to their inability to overcome biological barriers in the body and reach the cancer cells in sufficient concentrations. Houston Methodist nanotechnology and cancer researchers have solved this problem by developing a drug that generates nanoparticles inside the lung metastases in mice. In this study, 50 percent of the mice treated with the drug had no trace of metastatic disease after eight months. That’s equivalent to about 24 years of long-term survival following metastatic disease for humans. Due to the body’s own defense mechanisms, most cancer drugs are absorbed into healthy tissue causing negative side effects, and only a fraction of the administered drug actually reaches the tumor, making it less effective, says Mauro Ferrari, Ph.D, president and CEO of the Houston Methodist Research Institute. This new treatment strategy enables sequential passage of the biological barriers to transport the killing agent into the heart of the cancer. The active drug is only released inside the nucleus of the metastatic disease cell, avoiding the multidrug resistance mechanism of the cancer cells. This strategy effectively kills the tumor and provides significant therapeutic benefit in all mice, including long-term survival in half of the animals. This finding comes 20 years after Ferrari started his work in nanomedicine. Ferrari and Haifa Shen, M.D., Ph.D., are co-senior authors on the paper, which describes the action of the injectable nanoparticle generator (iNPG), and how a complex method of transporting a nano-version of a standard chemotherapy drug led to never before seen results in mice models with triple negative breast cancer that had metastasized to the lungs. “This may sound like science fiction, like we’ve penetrated and destroyed the Death Star, but what we discovered is transformational. We invented a method that actually makes the nanoparticles inside the cancer and releases the drug particles at the site of the cellular nucleus. With this injectable nanoparticle generator, we were able to do what standard chemotherapy drugs, vaccines, radiation, and other nanoparticles have all failed to do,” says Ferrari. Houston Methodist has developed good manufacturing practices (GMP) for this drug and plans to fast-track the research to obtain FDA-approval and begin safety and efficacy studies in humans in 2017. “I would never want to overpromise to the thousands of cancer patients looking for a cure, but the data is astounding,” says Ferrari, senior associate dean and professor of medicine, Weill Cornell Medicine. “We’re talking about changing the landscape of curing metastatic disease, so it’s no longer a death sentence.” The Houston Methodist team used doxorubicin, a cancer therapeutic that has been used for decades but has adverse side effects to the heart and is not an effective treatment against metastatic disease. In this study, doxorubicin was packaged within the injectable nanoparticle generator that is made up of many components. Shen, a senior member of the department of nanomedicine at Houston Methodist Research Institute, explains that each component has a specific and essential role in the drug delivery process. The first component is the nanoporous silicon material that naturally degrades in the body. The second component is a polymer made up of multiple strands that contain doxorubicin. Once inside the tumor, the silicon material degrades, releasing the strands. Due to natural thermodynamic forces, these strands curl-up to form nanoparticles that are taken up by the cancer cells. Once inside the cancer cells, the acidic pH close to the nucleus causes the drug to be released from the nanoparticles. Inside the nucleus, the active drug acts to kill the cell. “If this research bears out in humans and we see even a fraction of this survival time, we are still talking about dramatically extending life for many years. That’s essentially providing a cure in a patient population that is now being told there is none,” says Ferrari, who holds the Ernest Cockrell Jr. Presidential Distinguished Chair and is considered one of the founders of nanomedicine and oncophysics (physics of mass transport within a cancer lesion). The Houston Methodist team is hopeful that this new drug could help cancer physicians cure lung metastases from other origins, and possibly primary lung cancers as well. Additional researchers who collaborated with Ferrari and Shen on the Nature Biotechnology paper were: Rong Xu, Guodong Zhang, Junhua Mai, Xiaoyong Deng, Victor Segura-Ibarra, Suhong Wu, Jianliang Shen, Haoran Liu, Zhenhua Hu, Lingxiao Chen, Yi Huang, Eugene Koay, Yu Huang, Elvin Blanco, and Xuewu Liu (Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas); Jun Liu (Department of Pathology and Laboratory Medicine, The University of Texas-Houston Medical School); and Joe Ensor (Houston Methodist Cancer Center, Houston, Texas). The work was supported by grants from Department of Defense (W81XWH-09-1-0212 and W81XWH-12-1-0414), National Institute of Health (U54CA143837 and U54CA151668), and The Cockrell Foundation. Source: Houston Methodist Research Institute


Home > Press > Injectable nanoparticle generator could radically transform metastatic cancer treatment: Landmark preclinical study cured lung metastases in 50 percent of breast cancers by making nanoparticles inside the tumor Abstract: A team of investigators from Houston Methodist Research Institute may have transformed the treatment of metastatic triple negative breast cancer by creating the first drug to successfully eliminate lung metastases in mice. This landmark study appears today in Nature Biotechnology (early online edition). The majority of cancer deaths are due to metastases to the lung and liver, yet there is no cure. Existing cancer drugs provide limited benefit due to their inability to overcome biological barriers in the body and reach the cancer cells in sufficient concentrations. Houston Methodist nanotechnology and cancer researchers have solved this problem by developing a drug that generates nanoparticles inside the lung metastases in mice. In this study, 50 percent of the mice treated with the drug had no trace of metastatic disease after eight months. That's equivalent to about 24 years of long-term survival following metastatic disease for humans. Due to the body's own defense mechanisms, most cancer drugs are absorbed into healthy tissue causing negative side effects, and only a fraction of the administered drug actually reaches the tumor, making it less effective, said Mauro Ferrari, Ph.D, president and CEO of the Houston Methodist Research Institute. This new treatment strategy enables sequential passage of the biological barriers to transport the killing agent into the heart of the cancer. The active drug is only released inside the nucleus of the metastatic disease cell, avoiding the multidrug resistance mechanism of the cancer cells. This strategy effectively kills the tumor and provides significant therapeutic benefit in all mice, including long-term survival in half of the animals. This finding comes 20 years after Ferrari started his work in nanomedicine. Ferrari and Haifa Shen, M.D., Ph.D., are co-senior authors on the paper, which describes the action of the injectable nanoparticle generator (iNPG), and how a complex method of transporting a nano-version of a standard chemotherapy drug led to never before seen results in mice models with triple negative breast cancer that had metastasized to the lungs. "This may sound like science fiction, like we've penetrated and destroyed the Death Star, but what we discovered is transformational. We invented a method that actually makes the nanoparticles inside the cancer and releases the drug particles at the site of the cellular nucleus. With this injectable nanoparticle generator, we were able to do what standard chemotherapy drugs, vaccines, radiation, and other nanoparticles have all failed to do," said Ferrari. Houston Methodist has developed good manufacturing practices (GMP) for this drug and plans to fast-track the research to obtain FDA-approval and begin safety and efficacy studies in humans in 2017. "I would never want to overpromise to the thousands of cancer patients looking for a cure, but the data is astounding," said Ferrari, senior associate dean and professor of medicine, Weill Cornell Medicine. "We're talking about changing the landscape of curing metastatic disease, so it's no longer a death sentence." The Houston Methodist team used doxorubicin, a cancer therapeutic that has been used for decades but has adverse side effects to the heart and is not an effective treatment against metastatic disease. In this study, doxorubicin was packaged within the injectable nanoparticle generator that is made up of many components. Shen, a senior member of the department of nanomedicine at Houston Methodist Research Institute, explains that each component has a specific and essential role in the drug delivery process. The first component is the nanoporous silicon material that naturally degrades in the body. The second component is a polymer made up of multiple strands that contain doxorubicin. Once inside the tumor, the silicon material degrades, releasing the strands. Due to natural thermodynamic forces, these strands curl-up to form nanoparticles that are taken up by the cancer cells. Once inside the cancer cells, the acidic pH close to the nucleus causes the drug to be released from the nanoparticles. Inside the nucleus, the active drug acts to kill the cell. "If this research bears out in humans and we see even a fraction of this survival time, we are still talking about dramatically extending life for many years. That's essentially providing a cure in a patient population that is now being told there is none," said Ferrari, who holds the Ernest Cockrell Jr. Presidential Distinguished Chair and is considered one of the founders of nanomedicine and oncophysics (physics of mass transport within a cancer lesion). The Houston Methodist team is hopeful that this new drug could help cancer physicians cure lung metastases from other origins, and possibly primary lung cancers as well. ### Additional researchers who collaborated with Ferrari and Shen on the Nature Biotechnology paper were: Rong Xu, Guodong Zhang, Junhua Mai, Xiaoyong Deng, Victor Segura-Ibarra, Suhong Wu, Jianliang Shen, Haoran Liu, Zhenhua Hu, Lingxiao Chen, Yi Huang, Eugene Koay, Yu Huang, Elvin Blanco, and Xuewu Liu (Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas); Jun Liu (Department of Pathology and Laboratory Medicine, The University of Texas-Houston Medical School); and Joe Ensor (Houston Methodist Cancer Center, Houston, Texas). The work was supported by grants from Department of Defense (W81XWH-09-1-0212 and W81XWH-12-1-0414), National Institute of Health (U54CA143837 and U54CA151668), and The Cockrell Foundation. Nature Biotechnology is the highest rated publication in the Nature family of journals, with an impact factor of 41.5. For more information, please click If you have a comment, please us. Issuers of news releases, not 7th Wave, Inc. or Nanotechnology Now, are solely responsible for the accuracy of the content.


Cagle P.T.,Houston Methodist Hospital | Allen T.C.,University of Houston | Bernicker E.H.,Houston Methodist Cancer Center | Ge Y.,Houston Methodist Hospital | And 2 more authors.
Archives of Pathology and Laboratory Medicine | Year: 2016

Landmark events in the field of lung cancer in the past year have the potential to significantly alter the practice of pathology. Three key events are (1) approval of payment for low-dose computed tomography screening for lung cancer, (2) publication of an extensively revised World Health Organization classification of lung cancers, and (3) approval of immunohistochemistry based companion diagnostics by the US Food and Drug Administration. We briefly review these milestones in the context of their impact on the practice of pathology.


Horwitz S.,Sloan Kettering Cancer Center | Coiffier B.,Hospices Civils de Lyon | Foss F.,Yale Cancer Center | Prince H.M.,University of Melbourne | And 11 more authors.
Annals of Oncology | Year: 2015

Background: For patients with peripheral T-cell lymphoma (PTCL), the value of 18fluoro-deoxyglucose positron emission tomography (FDG-PET) scans for assessing prognosis and response to treatment remains unclear. The utility of FDG-PET, in addition to conventional radiology, was examined as a planned exploratory end point in the pivotal phase 2 trial of romidepsin for the treatment of relapsed/refractory PTCL. Patients and methods: Patients received romidepsin at a dose of 14 mg/m2 on days 1, 8, and 15 of 28-day cycles. The primary end point was the rate of confirmed/unconfirmed complete response (CR/CRu) as assessed by International Workshop Criteria (IWC) using conventional radiology. For the exploratory PET end point, patients with at least baseline FDG-PET scans were assessed by IWC + PET criteria. Results: Of 130 patients, 110 had baseline FDG-PET scans, and 105 were PET positive at baseline. The use of IWC + PET criteria increased the objective response rate to 30% compared with 26% by conventional radiology. Durations of response were well differentiated by both conventional radiology response criteria [CR/CRu versus partial response (PR), P = 0.0001] and PET status (negative versus positive, P < 0.0001). Patients who achieved CR/CRu had prolonged progression-free survival (PFS, median 25.9 months) compared with other response groups (P = 0.0007). Patients who achieved PR or stable disease (SD) had similar PFS (median 7.2 and 6.3 months, respectively, P = 0.6427). When grouping PR and SD patients by PET status, patients with PET-negative versus PET-positive disease had a median PFS of 18.2 versus 7.1 months (P = 0.0923). Conclusion(s): Routine use of FDG-PET does not obviate conventional staging, but may aid in determining prognosis and refine response assessments for patients with PTCL, particularly for those who do not achieve CR/CRu by conventional staging. The optimal way to incorporate FDG-PET scans for patients with PTCL remains to be determined. Trial registration: NCT00426764. © The Author 2015.

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