Houston, TX, United States
Houston, TX, United States

Time filter

Source Type

Kelly K.R.,University of Texas Health Science Center at San Antonio | Shea T.C.,University of North Carolina at Chapel Hill | Goy A.,Hackensack University Medical Center | Berdeja J.G.,Sarah Cannon Research Institute | And 8 more authors.
Investigational New Drugs | Year: 2014

Purpose: Amplification or over-expression of the mitotic Aurora A kinase (AAK) has been reported in several heme-lymphatic malignancies. MLN8237 (alisertib) is a novel inhibitor of AAK that is being developed for the treatment of advanced malignancies. The objectives of this phase I study were to establish the safety, tolerability, and pharmacokinetic profiles of escalating doses of MLN8237 in patients with relapsed or refractory heme-lymphatic malignancies. Methods: Sequential cohorts of patients received MLN8237 orally as either a powder-in-capsule (PIC) or enteric-coated tablet (ECT) formulation. Patients received MLN8237 PIC 25-90 mg for 14 or 21 consecutive days plus 14 or 7 days' rest, respectively, or MLN8237 ECT, at a starting dose of 40 mg/day once-daily (QD) for 14 days plus 14 days' rest, all in 28-day cycles. Subsequent cohorts received MLN8237 ECT 30-50 mg twice-daily (BID) for 7 days plus 14 days' rest in 21-day cycles. Results: Fifty-eight patients were enrolled (PIC n=28, ECT n=30). The most frequent grade ≥3 drug-related toxicities were neutropenia (45 %), thrombocytopenia (28 %), anemia (19 %), and leukopenia (19 %). The maximum tolerated dose on the ECT 7-day schedule was 50 mg BID. The terminal half-life of MLN8237 was approximately 19 h. Six (13 %) patients achieved partial responses and 13 (28 %) stable disease. Conclusion: The recommended phase II dose of MLN8237 ECT is 50 mg BID for 7 days in 21-day cycles, which is currently being evaluated as a single agent in phase II/III trials in patients with peripheral T-cell lymphoma. © 2013 The Author(s).


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.


News Article | October 26, 2016
Site: www.biologynews.net

Researchers at Houston Methodist have developed an artificial intelligence (AI) software that reliably interprets mammograms, assisting doctors with a quick and accurate prediction of breast cancer risk. According to a new study published in Cancer (early online Aug. 29), the computer software intuitively translates patient charts into diagnostic information at 30 times human speed and with 99 percent accuracy. "This software intelligently reviews millions of records in a short amount of time, enabling us to determine breast cancer risk more efficiently using a patient's mammogram. This has the potential to decrease unnecessary biopsies," says Stephen T. Wong, Ph.D., P.E., chair of the Department of Systems Medicine and Bioengineering at Houston Methodist Research Institute. The team led by Wong and Jenny C. Chang, M.D., director of the Houston Methodist Cancer Center used the AI software to evaluate mammograms and pathology reports of 500 breast cancer patients. The software scanned patient charts, collected diagnostic features and correlated mammogram findings with breast cancer subtype. Clinicians used results, like the expression of tumor proteins, to accurately predict each patient's probability of breast cancer diagnosis. In the United States, 12.1 million mammograms are performed annually, according to the Centers for Disease Control and Prevention (CDC). Fifty percent yield false positive results, according to the American Cancer Society (ACS), resulting in one in every two healthy women told they have cancer. Currently, when mammograms fall into the suspicious category, a broad range of 3 to 95 percent cancer risk, patients are recommended for biopsies. Over 1.6 million breast biopsies are performed annually nationwide, and about 20 percent are unnecessarily performed due to false-positive mammogram results of cancer free breasts, estimates the ACS. The Houston Methodist team hopes this artificial intelligence software will help physicians better define the percent risk requiring a biopsy, equipping doctors with a tool to decrease unnecessary breast biopsies. Manual review of 50 charts took two clinicians 50-70 hours. AI reviewed 500 charts in a few hours, saving over 500 physician hours. "Accurate review of this many charts would be practically impossible without AI," says Wong.


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.


News Article | March 16, 2016
Site: www.cemag.us

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


PubMed | Monash University, Goethe University Frankfurt, August Pi i Sunyer Institute for Biomedical Research, Novartis and 5 more.
Type: Clinical Trial, Phase I | Journal: Cancer | Year: 2016

NVP-AUY922 (AUY; Luminespib) with or without bortezomib showed preclinical activity against multiple myeloma (MM) cells. This phase 1/1B study assessed NVP-AUY922 alone and with bortezomib in patients with relapsed or refractory MM.Dose escalation was guided by an adaptive Bayesian logistic regression model. In phase 1, patients who progressed after 2 to 4 prior therapies received NVP-AUY922 intravenously once weekly. In phase 1B, patients who progressed after 2 or fewer prior therapies received NVP-AUY922 plus bortezomib. The primary objective was to determine the maximum tolerated dose (MTD) of NVP-AUY922.Twenty-four patients received NVP-AUY922 monotherapy at doses of 8 to 70 mg/m(2) . One dose-limiting toxicity (DLT) was observed (grade 3 blurred vision at 70 mg/m(2) ); no MTD was reached. The recommended phase 2 dose was 70 mg/m(2) . The most frequent drug-related adverse events (AEs) were diarrhea, nausea, and ocular toxicities. Grade 3/4 AEs were uncommon (<10%). Eight patients discontinued treatment because of AEs; 5 had ocular toxicities (45 mg/m(2) ). The best response was stable disease in 66.7% of the patients. There were no partial or complete responses. Five patients received NVP-AUY922 (which was started at 50 mg/m(2) ) plus bortezomib (1.3 mg/m(2) ). Three of these patients experienced DLT. No further dose escalation was performed; the MTD for NVP-AUY922 plus bortezomib was not established.This study showed disease stabilization with NVP-AUY922 in patients with relapsed or refractory MM. The MTD for NVP-AUY922 was not reached, but reversible ocular toxicity has been reported at high dose levels. Bortezomib at the standard recommended dose plus NVP-AUY922 was not tolerated.


PubMed | Medical College of Wisconsin, Baylor College of Medicine, Rush University Medical Center and Houston Methodist Cancer Center
Type: Journal Article | Journal: Clinical lymphoma, myeloma & leukemia | Year: 2016

For patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), autologous hematopoietic cell transplantation (auto-HCT) is commonly used. After auto-HCT, DLBCL patients are often monitored with surveillance imaging. However, there is little evidence to support this practice.We performed a multicenter retrospective study of DLBCL patients who underwent auto-HCT (n= 160), who experienced complete remission after transplantation, and who then underwent surveillance imaging. Of these, only 45 patients experienced relapse after day+100 after auto-HCT, with relapse detected by routine imaging in 32 (71%) and relapse detected clinically in 13 (29%).Baseline patient characteristics were similar between the 2 groups. Comparing the radiographic and clinically detected relapse groups, the median time from diagnosis to auto-HCT (389 days vs. 621 days, P= .06) and the median follow-up after auto-HCT (2464 days vs. 1593 days P= .60) were similar. The median time to relapse after auto-HCT was 191 days in radiographically detected relapses compared to 492 days in clinically detected relapses (P= .35), and median postrelapse survival was 359 days in such patients compared to 123 days in patients with clinically detected relapse (P= .36). However, the median posttransplantation overall survival was not significantly different for patients with relapse detected by routine imaging versus relapse detected clinically (643 vs. 586 days, P= .68).A majority (71%) of DLBCL relapses after auto-HCT are detected by routine surveillance imaging. Overall, there appears to be limited utility for routine imaging after auto-HCT except in select cases where earlier detection and salvage therapy with allogeneic HCT is a potential option.


PubMed | Oncosalud, Yale University, Houston Methodist Cancer Center, Foundation Medicine and 2 more.
Type: Journal Article | Journal: Science translational medicine | Year: 2016

Amplifications at 9p24 have been identified in breast cancer and other malignancies, but the genes within this locus causally associated with oncogenicity or tumor progression remain unclear. Targeted next-generation sequencing of postchemotherapy triple-negative breast cancers (TNBCs) identified a group of 9p24-amplified tumors, which contained focal amplification of the Janus kinase 2 (JAK2) gene. These patients had markedly inferior recurrence-free and overall survival compared to patients with TNBC without JAK2 amplification. Detection of JAK2/9p24 amplifications was more common in chemotherapy-treated TNBCs than in untreated TNBCs or basal-like cancers, or in other breast cancer subtypes. Similar rates of JAK2 amplification were confirmed in patient-derived TNBC xenografts. In patients for whom longitudinal specimens were available, JAK2 amplification was selected for during neoadjuvant chemotherapy and eventual metastatic spread, suggesting a role in tumorigenicity and chemoresistance, phenotypes often attributed to a cancer stem cell-like cell population. In TNBC cell lines with JAK2 copy gains or amplification, specific inhibition of JAK2 signaling reduced mammosphere formation and cooperated with chemotherapy in reducing tumor growth in vivo. In these cells, inhibition of JAK1-signal transducer and activator of transcription 3 (STAT3) signaling had little effect or, in some cases, counteracted JAK2-specific inhibition. Collectively, these results suggest that JAK2-specific inhibitors are more efficacious than dual JAK1/2 inhibitors against JAK2-amplified TNBCs. Furthermore, JAK2 amplification is a potential biomarker for JAK2 dependence, which, in turn, can be used to select patients for clinical trials with JAK2 inhibitors.


PubMed | The Texas Institute, University of Houston and Houston Methodist Cancer Center
Type: Journal Article | Journal: Nature biotechnology | Year: 2016

The efficacy of cancer drugs is often limited because only a small fraction of the administered dose accumulates in tumors. Here we report an injectable nanoparticle generator (iNPG) that overcomes multiple biological barriers to cancer drug delivery. The iNPG is a discoidal micrometer-sized particle that can be loaded with chemotherapeutics. We conjugate doxorubicin to poly(L-glutamic acid) by means of a pH-sensitive cleavable linker, and load the polymeric drug (pDox) into iNPG to assemble iNPG-pDox. Once released from iNPG, pDox spontaneously forms nanometer-sized particles in aqueous solution. Intravenously injected iNPG-pDox accumulates at tumors due to natural tropism and enhanced vascular dynamics and releases pDox nanoparticles that are internalized by tumor cells. Intracellularly, pDox nanoparticles are transported to the perinuclear region and cleaved into Dox, thereby avoiding excretion by drug efflux pumps. Compared to its individual components or current therapeutic formulations, iNPG-pDox shows enhanced efficacy in MDA-MB-231 and 4T1 mouse models of metastatic breast cancer, including functional cures in 40-50% of treated mice.

Loading Houston Methodist Cancer Center collaborators
Loading Houston Methodist Cancer Center collaborators