Researcher finds thyroid cancer gene inhibits spread of malignant cells

A mutant gene long thought to accelerate tumor growth in thyroid cancer patients actually inhibits the spread of malignant cells, showing promise for novel cancertherapies, a Mayo Clinic study has found. The findings will be presented by Mayo Clinic researcher Honey Reddi, Ph.D., at the Endocrine Society meeting in Boston.

Dr. Reddi's discovery could have widespread implications in cancer research andendocrinology. It could help oncologists sharpen the diagnosis of specific types of thyroid cancers, while leading pharmaceutical researchers toward therapeutics derived from a protein once thought to feed tumor growth.

"It's not an oncogene like everyone thought it was," Dr. Reddi says, referring to a genewith the potential to cause cancer. "We all knew what happened in the cell culture, but we said, 'That's not good enough,' so we asked, 'What would it do in mice?'"

Thyroid cancer is the sixth most common cancer in the world, and 15 to 20 percent of all thyroid cancer cases are follicular, a type that is more aggressive. Dr. Reddi's findings could aid this diagnosis and treatment for thousands of patients.

Distinguishing benign from malignant follicular thyroid cancer poses a unique challenge to oncologists. An accurate diagnosis of malignant follicular cancer cannot be made until after cancerous material is removed. That has led to countless unnecessary surgeries in patients with benign thyroid tumors. Patients who now present with non-papillary cancerous growths on thyroid cells must undergo surgery to remove the tumor — even if the cancer is benign.

Dr. Reddi's research found that the PAX8/PPARγ fusion protein, developed from a mutated fusion gene found in many follicular thyroid carcinomas, functions as a tumor suppressor by upregulating (encourages natural production of) microRNA-122 and PTEN, both naturally occurring anti-tumor agents.

PAX8/PPARγ results from the translocation of genetic material between humanchromosomes 2 and 3. Previous in vitro studies of the PAX8/PPARγ protein found rapid acceleration of cell growth, which led researchers to the false interpretation that PAX8/PPARγ functioned as an oncogene, a type of mutated gene that encourages tumor propagation, Dr. Reddi says.
Mayo Clinic's in vivo animal studies show that PAX8/PPARγ upregulates the well-known anti-cancer protein PTEN, as well as microRNA-122, and likely facilitates other cancer-fighting molecules.
PAX8/PPARγ does not boost tumor progression when exposed to cancerous cells, Dr. Reddi says. Rather, its facilitation of other native anti-cancer molecules appears to outweigh the tumor propagation. Tumors grew about four times slower in mice exposed to the PAX8/PPARγ gene than those who were deprived of the protein's cancer-fighting qualities.
Among the team's goals in future research is the identification of other microRNA-like markers, which could identify a benign disease and obviate the need for immediate and unnecessary surgery.
Based on her discussions with clinicians at Mayo Clinic, Dr. Reddi says, "There are many complications from thyroid surgery, and having early detection markers could save thousands of unnecessary surgeries every year. We're just getting started and look towards a rapid translation from bench to bedside."
Source: Mayo Clinic

“Broad spectrum” cancer suppressor gene discovered

Portuguese researchers have discovered a "broad spectrum" cancer suppressor gene - called LRP1B – which acts by removing proteins crucial for cancer development from the tumour environment. The fact that LRP1B does not act on the tumour itself (in this study thyroid tumours) but, instead, on molecules which are known to be important to many different cancers is what makes it so interesting. Because this means that LRP1B, and also therapies capable of inducing it (or mimicking its effect), could, in theory, be used to treat a variety of cancers. The study by Hugo Prazeres and Paula Soares from IPATIMUP and University of Porto along with colleagues Fernando Rodrigues and Teresa Martins from Portuguese Institute of Oncology, Coimbra was just published in the journal Oncogene(1).

LRP1B is a protein/receptor on the cell membrane with the function to carry molecules from outside to the inside of the cell. But a 2010 study looking for mutated genes in 3312 patients with 26 different cancers showed that LRP1B was one of the 10 most frequently found deleted genes triggering the interest of researchers by suggesting that the receptor could play a role in cancer.

To investigate this possibility Prazeres, Soares and colleagues looked into the thyroid gland where LRP1B is normally found in high quantities. Thyroid cancer was also one of those with LRP1B deletions in the 2010 study and, even more interesting, a still unidentified susceptibility gene is known to be localised in same chromosomal area of LRP1B. And in fact, all the thyroid cancer samples analysed by Prazeres and colleagues - whether from patients with familial (inherited) or sporadic (non-inherited) thyroid cancers – turned out to have abnormally low levels of LRP1B. This suggested that the loss of LRP1B was linked to the appearance of cancer. Two other experiments supported this idea. First a comparison of normal and cancerous thyroid tissues showed that the less LRP1B a thyroid cancer had, the more aggressive it seemed to be. And when the researchers re-inserted LRP1B into the cancerous cells they saw how the new LRP1B positive cells lost much of their capacity to divide and invade new tissues (so in effect their capacity to form metastasis, the deadly marker of cancer).

Once the link LRP1B /cancer prevention was established the next step was to understand how this occurred.

Since LRP1B function is to transport molecules from the outside to the inside of the cells the researchers hypothesised that LRP1B could be removing one or more molecules important for tumour development from around the cancer cells. To test that Prazeres and Soares compared the composition of the environment around cells with or without LRP1B and discovered much lower quantities of a protein called matrix metalloproteinase (MMP) on those with LRP1B. MMP breaks down other proteins and, in cancers, is known to destroy the (protein) matrix, which gives cells structural support in the tissues. By destroying the matrix MMP allows the tumours space and “freedom” to expand and invade other tissues and MMP disappearance can explain LRP1B effects stopping tumour development. Interestingly LRP1B is also known to affect uPA another protein involved with MMP in the destruction of the cellular matrix.

Prazeres and Soares also looked into the mechanism behind LRP1B loss and found a surprising combination of mechanisms. In fact, either the LRP1B gene (or parts of it) have been deleted, or the gene was methylated (a chemical group called methyl binds to LRP1B blocking access to molecules that activate it) or the gene was being suppressed by a micro RNA. MicroRNAs are small RNAs that instead of being used as "information carriers" act by activating or suppressing other genes (normally RNA carries information from the DNA to be used as blueprint to make proteins). In the case of the thyroid cancers analysed by Prazeres and colleagues a microRNA that suppresses LRP1B was found in aberrantly high quantities. This data is particularly important if one day scientists attempt to develop treatments capable of restoring LRP1B and its cancer “watchdog” functions

In conclusion, Prazeres and Soares’ study reveals a new tumour suppressor gene - LRP1B - that acts by changing the tumour microenvironment, or, more specifically, by removing a receptor crucial for tumour development called MMP. And because most tumours depend on MMP to grow and invade other tissues this means that a large number of cancers can potentially be controlled by LRP1B. It also suggests that treatments capable of increase this receptor (or reproduce its effect) could be used against several types of cancer including lung, esophagus, breast, hepatocellular, renal, neural and colorectal cancer (to name just a few of those already linked to LRP1B loss).

So, where next? “Future works - says Paula Soares the group leader - is already on course to identify if other extracellular molecules are affected by changes in LRP1B and what exactly is happening inside the cell too. Also if this protein is in fact confirmed to be deleted in multiple cancers - like others and also our group have suggested - then strategies based on decoy proteins –proteins with the same function of LRP1B – could be developed to restored normal conditions."

(1) Oncogene (2011) 30, 1302–1317; doi:10.1038/onc.2010.512;

Chromosomal, epigenetic and microRNA-mediated inactivation of LRP1B, a modulator of the extracellular environment of thyroid cancer cells

http://www.nature.com/onc/journal/v30/n11/abs/onc2010512a.html

camorim is based in Oxford, England, United Kingdom, and is Anchor for Allvoices

Thyroid Cancer Types, Stages and Treatment Overview

Thyroid Cancer Types, Stages and Treatment Overview

Stages of Thyroid Cancer - Avvo.com

Doctors categorize thyroid cancer into stages, based on tumor size and location, as well as how far cancer cells have spread. For papillary and follicular thyroid cancers, age is also considered. Knowing this information helps them choose appropriate treatments and evaluate how likely a cure is.

Thyroid cancer stages differ slightly, depending on the type.

Stages of Papillary and Follicular Thyroid Cancer

There are only two stages of these cancers for people under age 45 but four stages for those 45 and older.

Stage I: For patients under 45 years old, either:

• Cancer is present only in the thyroid, or
• Cancer has spread to tissues and lymph nodes near the thyroid

For patients 45 and older, a stage I tumor is no bigger than two centimeters and there is no cancer outside the thyroid.

Stage II: In patients under 45 years old, cancer cells are present in tissues far from the thyroid, like the lungs.

In patients 45 and older, a stage II tumor is between 2 and 4 centimeters. Cancer cells still have not spread out of the thyroid.

Stage III: One of the following is true:

• The tumor is bigger than 4 centimeters but has not spread out of the thyroid, or
• The tumor can be any size and cancer is present the lymph nodes or in tissues near the thyroid or both

Stage IV: Stage IV tumors are divided into subcategories:

• Stage IVA cancer has spread to lymph nodes in the neck or near the lungs, or it has spread to tissues like the esophagus, larynx, or the nerve to the larynx
• Stage IVB Cancer may have spread to the lymph nodes and has spread to tissues near the spine or to blood vessels around the heart or lungs
• Stage IVC cancer has spread farther, to organs like the lungs

Stages of Medullary Thyroid Cancer

Stage 0: At this stage, there is no visible tumor. The disease shows up on a special screening test.

Stage I: The tumor is no bigger than 2 centimeters and is confined to the thyroid

Stage II: Either:

• The tumor is bigger than 2 centimeters but has not spread outside the thyroid, or
• The cancer has spread right outside the thyroid, but has not reached the lymph nodes

Stage III: At this stage, tumor size doesn’t matter. Cancer cells are growing in nearby lymph nodes and possibly in other nearby tissues.

Stage IV: Stage IV medullary thyroid cancer is also divided into three substages.

• Stage IVA: Either:
• The tumor has spread to tissues like the esophagus or larynx, and possibly nearby lymph nodes, or
• Cancer has spread just outside the thyroid and to lymph nodes in the neck or near the lungs
• Stage IVB: Cancer can be present in the lymph nodes and the cancer has spread to tissues near the spine or to blood vessels around the heart or lungs
• Stage IVC: Cancer has spread to distant organs

Stages of Anaplastic Thyroid Cancer

Anaplastic cancer is always Stage IV and is divided into three substages

Stage IVA cancer is in the thyroid and might also be in the lymph nodes

Stage IVB cancer is found in tissues right outside the thyroid and possibly also the lymph nodes

Stage IVC cancer has spread beyond the neck

Treatment of Palmar Plantar Erythrodysesthesia (PPE) With Topical Sildenafil - Full Text View - ClinicalTrials.gov

Clinical trial treating Hand-Foot Syndrome with Topical Sildenafil (i.e., topical Viagra)

Treatment of Palmar Plantar Erythrodysesthesia (PPE) With Topical Sildenafil - Full Text View - ClinicalTrials.gov: "Topical Sildenafil"

Hand Foot Syndrome Discussion With Dr Liqun Jia From The China-japan Friendship Hospital

Interesting discussion about Hand-Foot Syndrome and a Chinese herbal extract that seems to be of some help in clinical trials. (I wonder when, if ever, it will be even LOOKED at in the USA!) Video runs about 4-and-a-half minutes.

Hand Foot Syndrome Discussion With Dr Liqun Jia From The China-japan Friendship Hospital

Blood Pressure Rise Predicts Better Sunitinib Response

Patients who experience high blood pressure (BP) while being treated with sunitinib for advanced renal cell carcinoma (RCC) respond better to treatment, have improved overall survival, and have longer progression-free survival (PFS), according to a report in the Journal of the National Cancer Institute (2011;103;763-773).

Researchers analyzed four studies involving 5,461 patients with metastatic RCC treated with sunitinib 50 mg/day. Patients with sunitinib-induced hypertension—defined as a maximum systolic blood pressure (SBP) of 140 mm Hg or higher—survived nearly four times longer than those with lower maximum SBP (30.5 vs. 7.8 months). Similarly, those with maximum diastolic blood pressure (DBP) of 90 mm Hg or higher survived twice as long as those with lower DBP levels (32.2 vs. 14.9 months). PFS was 12.5 months in systolic hypertensive patients versus 2.5 months among those without hypertension. The PFS was 13.4 months for patients with diastolic hypertension and 5.3 months for those with no hypertension. The use of BP-lowering medication did not reduce the anti-tumor effectiveness of sunitinib.

Eisai releases lenvatinib Phase II trial preliminary results - Pharmaceutical Business Review

Eisai releases lenvatinib Phase II trial preliminary results

PBR Staff WriterPublished 02 June 2011

Eisai has released preliminary results from an open-label, global, single-arm Phase II study evaluating its multi-targeted kinase inhibitor lenvatinib (E7080).

The results from the trial showed an objective response rate (ORR) of 59% (34/58, 95% CI: 45-71), based on an updated investigator assessment, in patients with advanced radioiodine (RAI)-refractory differentiated thyroid cancer (DTC).

The involved around 58 patients with advanced RAI refractory DTC whose disease had progressed during the prior 12 months.

Currently, Eisai is engaged in advancing its products like Halaven, lenvatinib and farletuzumab (MORAb-003), for the treatment of breast, ovarian, thyroid, endometrial and other types of cancer in the women's oncology arena. 

Plexxikon Announces Combination Trials for Vemurafenib in Melanoma | EON: Enhanced Online News

Plexxikon Announces Combination Trials for Vemurafenib in Melanoma

New Phase 2 Trial Initiated to Study Vemurafenib as Single Agent in Thyroid Cancer

June 02, 2011 07:03 AM Eastern Daylight Time

BERKELEY, Calif.--(EON: Enhanced Online News)--Plexxikon Inc., a member of the Daiichi Sankyo Group, today announced new clinical trials in metastatic melanoma testing vemurafenib (PLX4032/RG7204) in combination with other state-of-the-art treatments, including an immunologic therapy and an investigational MEK inhibitor. Additionally, a new trial will test vemurafenib as a single agent in thyroid cancer patients who have the BRAF mutation. Vemurafenib targets the mutant BRAF protein, which is present in about half of melanomas, about 40-70 percent of thyroid cancer and about eight percent of all solid tumors.

“Vemurafenib has demonstrated consistent and positive results to-date as a single agent, and represents a potential new, important treatment option for melanoma patients. By combining vemurafenib with other scientifically rational agents, we hope to further enhance patient treatment outcomes”

“Vemurafenib has demonstrated consistent and positive results to-date as a single agent, and represents a potential new, important treatment option for melanoma patients. By combining vemurafenib with other scientifically rational agents, we hope to further enhance patient treatment outcomes,” said K. Peter Hirth, Ph.D., chief executive officer of Plexxikon. “We are equally excited about exploring vemurafenib treatment in other BRAF-mutant tumor types, particularly thyroid cancer, given the compelling signal for this cancer seen in our Phase 1 dose-escalation trial.”

About Combination Studies with Vemurafenib for Metastatic Melanoma

Earlier this year, a trial evaluating vemurafenib treatment with another investigational candidate, an oral agent targeting MEK kinase inhibitor, GDC-0973, was initiated in metastatic melanoma patients with the BRAF mutation. The addition of GDC-0973 to vemurafenib treatment in this study will enable evaluation as to whether the inhibition of two key parts of the BRAF/MEK cancer cell signaling pathway can improve treatment outcomes for patients, including potentially extending response duration. This trial is expected to enroll approximately 50 patients, with the goal of establishing safety, tolerability and activity of the two drugs given in combination.

Another trial testing vemurafenib treatment with an immunologic antibody infusion therapy for metastatic melanoma is also planned.

About Thyroid Cancer Trial with Vemurafenib

Also recently, a Phase 2 trial has been initiated to evaluate vemurafenib in refractory papillary thyroid cancer. In this trial, approximately 40 thyroid cancer patients with the BRAF mutation will receive vemurafenib at 960 mg BID. The primary endpoint for this study is best overall response rate. In the previous Phase 1 dose escalation trial, three thyroid patients were enrolled and treated at various lower dose levels. All three patients demonstrated activity of the drug as assessed by tumor shrinkage and prolonged stable disease.

About Vemurafenib (PLX4032)

Vemurafenib is a novel, oral small molecule being developed for the treatment of melanoma and other cancers harboring the oncogenic BRAF mutation. Plexxikon utilized its structure-guided chemistry platform to discover vemurafenib, and initiated clinical development in 2006. Plexxikon and Roche signed a license and collaboration agreement in 2006 to co-develop vemurafenib. A DNA-based companion diagnostic to identify patients whose tumors carry the BRAF mutation also is being co-developed by Roche and Plexxikon in parallel with the therapeutic development of vemurafenib.

Current studies of vemurafenib are being conducted by Roche, Plexxikon and Genentech, a member of the Roche Group. Plexxikon recently announced the submission of applications for market approval for vemurafenib in the U.S. and Europe. During the marketing application review period, vemurafenib is available to eligible patients with BRAF^V600 mutation-positive melanoma through a global patient access program. More information about this program or other vemurafenib studies is available at www.clinicaltrials.gov (in the U.S.) or www.clinicaltrialsregister.eu or on the Roche Clinical Trials Registry at www.roche-trials.com (in the EU). Genentech can also be contracted by calling the company’s clinical trial call center at 888-662-6728 or emailing genentech@druginfo.com.

About Plexxikon

Plexxikon, a member of the Daiichi Sankyo Group, is a leader in the structure-guided discovery and development of novel small molecule pharmaceuticals to treat human disease. The company’s lead compound, vemurafenib (PLX4032), is in late-stage clinical trials for the treatment of melanoma, and the subject of recent applications for marketing approval in the U.S. and Europe. PLX3397, the company’s next oncology candidate, has advanced to Phase 2 testing. The company is developing a portfolio of clinical and preclinical stage compounds to address significant unmet medical needs in oncology, as well as in several other therapeutic indications. Plexxikon’s proprietary Scaffold-Based Drug Discovery™ platform integrates multiple state-of-the-art technologies, including structural screening as a key component that provides a significant competitive advantage over other drug discovery approaches. For more information, please visit www.plexxikon.com.