Posts Tagged ‘phase I’

Personalized medicine gearing up to tackle cancer

Reporter: Ritu Saxena, Ph.D.

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Views of leading cancer researcher, Dr. Apostolia M. Tsimberidou

Since the inception of personalized medicine, it has been visualized that a patient walking into a doctor’s office would be recommended a treatment tailored around his/her genetic and molecular profile. Although this idea of personalized medicine still seems far-fetched, it is currently being implemented in a few clinics, including that of Apostolia M. Tsimberidou, MD, PhD.

Dr. Tsimberidou is an associate professor in the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center and a member of the American Society of Clinical Oncology (ASCO) Educational Committee. She is also the brains behind a large study of personalized medicine-based cancer treatment. The findings of her successful phase I clinical trial in late-stage cancer patients has attracted a lot of attention. I recently had a chance to interview her and find out her views on the current status, challenges and future of personalized medicine.

Dr. Tsimberidou explains the basis of her study, “We analyze tumors from patients with cancer to identify molecular aberrations, which are then used to select optimal treatment.” On the basis of the molecular aberrations determined, the patients were recommended for treatment with matched anti-cancer therapeutic drugs. The results obtained in terms of clinical outcomes of patients were intriguing. Among patients harboring one molecular aberration, there was a significant improvement in the median survival duration of patients who underwent matched therapy (13.4 months) as compared to patients treated without matched therapy (9 months). Matched therapy patients also showed a better overall response rate of 27% vs. 5% in unmatched patients. Another criteria measured was the time-to-treatment failure which was again longer with matched targeted therapy, 5.2 months compared to 3.1 months with systemic therapy. The results of the study were published recently in Clinical Cancer Research. Essentially, the study concluded that there is a better chance of drug response and longer survival in patients who have been administered drugs according to their molecular signature. This is indeed good news for patients suffering from the disease.

So, how does the success of matched-therapy translate to the clinic? “What we propose is the optimization of treatment by taking into consideration multiple factors, including the genetics and molecular status of tumors, and that the process becomes a part of regular clinical practice,” explains Dr. Tsimberidou.

When Dr. Tsimberidou and her colleagues at MD Anderson Cancer Center started the phase I clinical trial for personalized medicine in 2007, they faced numerous challenges. The biggest challenge she describes was “dealing with the inertia of the existing system”. “It is easy for an insurance company to approve payment for a CAT-scan, but it is still challenging to cover the cost of a new biopsy and tumor molecular analysis from a patient who has suffered from cancer for over 10 years. Hopefully, there will be a shift in the approach.” How could a shift in the approach be achieved? “Researchers need to continue to carefully design prospective clinical trials, including small phase II clinical studies with targeted agents against tumor molecular aberrations.” She emphasizes that “resources–time, energy and funds–to conduct clinical trials are very limited. Using the approach of matched therapy earlier during the course of the disease could give better results.”

Dr. Tsimberidou states, “The most important thing is that we need to take advantage of the available technology to make advances in tumor molecular profiling and drug discovery. We need the technologists, molecular biologists, health care professionals and regulators to work together and expedite the use of the existing technology to identify tumor abnormalities and to discover novel drugs. We need to access, learn and share with each other to determine what the optimal therapeutic approach for every patient is.”

According to the American Cancer Society, the probability that an individual will develop or die from cancer over the course of a lifetime (lifetime risk) in the United States is less than a 1 in 2 for men; and a little more than 1 in 3 for women. Thanks to passionate and committed researchers like Dr. Tsimberidou, personalized medicine-based cancer treatments might take us a few steps closer to curing the disease.  Dr. Tsimberidou concludes, “We have to develop innovative treatment protocols and to offer the best treatment possible for each of our patients”.


Ritu Saxena, Ph.D.

Author, Reporter, Curator @ Leaders in Pharmaceutical Business Intelligence


Research article:

Personalized medicine in a phase I clinical trials program: the MD anderson cancer center initiative.

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Nanotech Therapy for Breast Cancer

Author/ Curator ; Tilda Barliya PhD

Breast cancer is the second most common cancer worldwide after lung cancer, the fifth most common cause of cancer death, and the leading cause of cancer death in women. The global burden of breast cancer exceeds all other cancers and the incidence rates of breast cancer are increasing (Jemel. A CA cancer J Clin 2010:60; 277-300). (Nature Reviews Clinical Oncology to coincide with the 2010 San Antonio Breast Cancer Symposiumhttp://www.nature.com/nrclinonc/focus/breast-cancer/index.html).

The heterogeneity of breast cancers makes them both a fascinating and challenging solid tumor to diagnose and treat. Triple-negative breast cancers in particular are difficult to define—this tumor subgroup lacks expression of HER2, the estrogen receptor and progesterone receptor and do not respond to hormonal therapies or HER2-targeted therapies (owing to the lack of expression of these targets)—and these tumors are associated with a poor prognosis; thus, new systemic therapies are desperately needed. Luca Gianni and coauthors review the evidence for the biology of this subtype, which shares genetic and morphologic similarities with the basal-like breast cancer subtype but also represents a biologically distinct subtype that is heterogeneous. They also discuss potential treatment options, including poly(ADP ribose) polymerase (PARP) inhibitors, which have shown promising efficacy and safety profiles in phase I and II clinical trials in patients with triple-negative breast cancer.

Breast cancers with a BRCA mutation leave the cell susceptible such that PARP inhibition combined with this genetic defect cannot repair DNA breaks resulting in cell death—an effect not observed in normal cells because the BRCA function compensates for PARP inhibition. Importantly, BRCA deficiency and sensitivity to PARP inhibition does not seem to be restricted to a particular histology but rather the BRCA genotype.

One of the greatest issues in oncology is tumor heterogeneity as well as the detection and validation of biomarkers that can aid in treatment decisions. As breast cancers represent a multitude of different diseases with intratumoral and intertumoral genetic and epigenetic alterations, the next challenge will be to understand how these defects arise during disease progression and learn more about the development of mechanisms of resistance to therapies. (Nature Reviews Clinical Oncology to coincide with the 2010 San Antonio Breast Cancer Symposiumhttp://www.nature.com/nrclinonc/focus/breast-cancer/index.html).

Generally, breast tumors are categorized into four different stages based upon their size, location, and evidence of metastasis (www.cancer.org).  Treatment options are also determined by the stage, hormone  (ER/PR), human epidermal growth factor receptor 2 (HER-2/neu) and gene (BRCA1) Status of breast tumors.

Many different types of nano-delivery systems with different materials and physio-chemical properties have been developed for application in breast cancer. We previously discussed in depth the application of liposomal doxorubicin, albumin-bound paclitaxel (Abraxane) and I’d like to shift the discussion to a completely different player in breast cancer progression TNF alpha.


Tumor necrosis factor-α (TNF-α) is an important pro-inflammatory cytokine in the development and progress in human cancer and was shown to induce mammary tumors through through the activation of p42/p44 MAPK, JNK, PI3-K/Akt pathways (http://www.ncbi.nlm.nih.gov/pubmed/18061162), (http://www.ncbi.nlm.nih.gov/pubmed/21476000). Among its roles, TNF-α  is thought to be pro-angiogenic. Paradoxically, it is also a potent anti-vascular cytokine at higher doses (it was named for its anti-tumor activity) and can be used clinically to destroy tumor vasculature. More so TNF-alpha is able to initiate cellular apoptosis and it is possible that these apoptotic pathways are deactivated in tumor cells (http://jbiol.com/content/8/9/85)

Unfortunately, TNF-α has powerful and toxic systemic side effects and has only limited uses at present. Much work is under way to devise ways of targeting TNF-α specifically to tumors.

A nanoparticle delivery system, consisting of PEG coated gold nanoparticle loaded with TNF-α, was constructed to maximize the tumor damage and minimize the systemic toxicity of TNF-α (Visaria et al 2006; Visaria RK, Griffi n RJ, Williams BW, et al. 2006. Enhancement of tumor thermal therapy using gold nanoparticle-assisted tumor necrosis factoralpha delivery. Mol Cancer Ther, 5:1014–20). Combination of local heating and nanoparticle-based delivery of TNF-α resulted in enhanced therapeutic effi cacy than either treatment alone.

Thermally-induced tumor growth delay was enhanced by pretreatment with the nanoparticle, when given intravenously at the proper dosage and timing. Tumor blood fl ow suppression, as well as tumor perfusion defects, suggested vascular damage-mediated tumor cell killing. Surprisingly, following intravenous administration, little to no accumulation in the RES (eg, liver and spleen) or other healthy organs of the animals was observed (Paciotti et al 2004).

Phase I clinical trials of this conjugate, subsequently termed “CYT-6091” also known as Aurmine (CytImmune Scientific Inc)(http://www.cytimmune.com/go.cfm?do=page.view&pid=26) are currently ongoing to evaluate its safety, pharmacokinetics, and clinical efficacy.(Visaria et al 2007; Visaria R, Bischof JC, Loren M, et al. 2007. Nanotherapeutics for enhancing thermal therapy of cancer. Int J Hyperthermia, 23:501–11.), (www.cytimmune.com/download/posters/ASCO_Poster.pdf)

Both TNF-a and thiolated polyethylene glycol (PEG-Thiol) are independently bound to the surface of 27 nm colloidal gold particles.

Clinical Trial Protocol:

Aim: CYT-6091 was tested in a phase I open label trial in solid tumor, advanced stage patients.

Patients (n = 3/dose), admitted to the NIH Clinical Center ICU, received two IV injections of CYT-6091 on day 0 and 14. Dosing started at 50 µg/m2 of TNF, up to 600 µg/m2. Vital signs were monitored and blood samples were drawn over 48 h.

  • The primary endpoint of the study was to determine the MTD for CYT-6091.
  • Secondary endpoints included PK, disease response (staged 45 days post treatment by RECIST), and the detection of gold nanoparticles in tumors and in adjacent healthy tissue.


  • Twenty-nine patients were treated. Even at the lowest dose (50 µg/m2), patients exhibited a febrile response, which was mitigated by acetaminophen and indomethacin pretreatment. None of the 29 patients treated with doses of 50-600 µg/m2 showed a DLT hypotensive response, and in fact, no DLT was seen.
  • T1/2 estimates for TNF, administered as CYT-6091, are 120, 131, 127, 146, 112, 113, 266, 371, and 160 minutes for 50, 100, 150, 200, 250, 300, 400, 500, 600 µg/m2, respectively (published T1/2 for native TNF is ~27 minutes).
  • In the 28 patients eligible for response assessment, there was 1 PR (100 µg/m2 dose, 7 months duration) and 3 SD (2, 2, and 3 months duration). Electron micrographs show gold nanoparticles in tumor biopsies


CYT-6091 is well tolerated at doses up to 600 µg/m2 of TNF, levels 3-times greater than the published MTD for native TNF. CYT-6091 targets tumors in humans. Efficacy studies in combination with chemotherapy are planned.

In summary, the phase I clinical trial used solid tumor patients to evaluate the safety of its use, breast cancer oncologists however, set their eyes on the target.


1. Jemel. A CA cancer J Clin 2010:60; 277-300

2. Nature Reviews Clinical Oncology to coincide with the 2010 San Antonio Breast Cancer Symposiumhttp://www.nature.com/nrclinonc/focus/breast-cancer/index.html

3. Visaria RK, Griffi n RJ, Williams BW, et al. 2006. Enhancement of tumor thermal therapy using gold nanoparticle-assisted tumor necrosis factoralpha delivery. Mol Cancer Ther, 5:1014–20

4. Visaria R, Bischof JC, Loren M, et al. 2007. Nanotherapeutics for enhancing thermal therapy of cancer. Int J Hyperthermia, 23:501–11.

5. http://nano.gov/sites/default/files/nanomedicine_-_tamarkin.pdf

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