cetuximab

AACR says that new drug may assist therapy for Head and Neck Cancer

Source: hcplive.com
Author: 
 

THURSDAY, Sept. 18, 2014 (HealthDay News) — The investigational drug alpelisib (previously known as BYL719) appears to inhibit activation of the pathway that leads to resistance to cetuximab, an anti-epidermal growth factor receptor agent used in the treatment of head and neck cancer. These findings were presented at the American Association for Cancer Research’s special conference “Targeting the PI3K-mTOR Network in Cancer,” held from Sept. 14 to 17 in Philadelphia.

Pamela Munster, MD, of the University of California in San Francisco, and colleagues tested the combination of BYL719 and cetuximab in vivo in a cetuximab-sensitive and a cetuximab-resistant xenograft model of esophageal squamous cell carcinoma. In a phase Ib study, BYL719 was administered in combination with cetuximab in adults with recurrent or metastatic squamous cell carcinoma of the head and neck that was resistant or intolerant to platinum-based chemotherapy; prior cetuximab therapy was allowed.

The researchers found that the addition of BYL719 to cetuximab showed an additive effect in the cetuximab-sensitive model. BYL719 restored sensitivity to cetuximab in the cetuximab-resistant model. In the phase Ib study, as of March 10, 2014, 37 patients have received BYL719 and cetuximab, and the overall response rate is 11%. Based on the data from preclinical studies and the phase Ib study, the combination of alpelisib and cetuximab for squamous cell carcinoma of the head and neck is being explored in a phase II study.

“Treatment resistance is often conveyed through activation of the PI3K/AKT/mTOR pathway, and alpelisib is an inhibitor of this pathway,” Munster said in a statement.

The study was funded by Novartis, the developer of alpelisib (BYL719).

*This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.
 
September, 2014|Oral Cancer News|

Targeted radiation, drug therapy combo less toxic for recurrent head, neck cancers

Source: medicalxpress.com
Author: University of Pittsburgh Schools of the Health Sciences

Patients with a recurrence of head and neck cancer who have previously received radiation treatment can be treated more quickly, safely and with fewer side effects with high doses of targeted radiation known as Stereotactic Body Radiation Therapy (SBRT) in combination with a drug that also carefully targets cancerous tumors. These findings from a UPMC CancerCenter study were presented today at the American Society of Radiation Oncology (ASTRO) annual meeting in San Francisco.

SBRT uses concentrated radiation beams in high doses to destroy tumors in difficult or hard-to-reach areas. The treatment is noninvasive, which minimizes damage to surrounding healthy tissue and organs. Clinicians at UPMC CancerCenter, partner with the University of Pittsburgh Cancer Institute (UPCI), used SBRT in combination with the drug cetuximab for patients who had a recurrence of squamous cell carcinoma of the head and neck after going through radiation.

“The prognosis for patients who have a recurrence of head and neck cancer that cannot be surgically removed is already poor. Traditional treatments can be associated with significant side effects so severe that patients give up on the therapy altogether,” said Dwight E. Heron, M.D., vice chairman of radiation oncology at UPCI and director of Radiation Oncology Services at UPMC CancerCenter. “By taking these patients through an abbreviated course of targeted drug and SBRT, we minimize the side effects of treatment.”

Doctors treated 48 patients with the combination therapy between July 2007 and March 2013. All of the patients were able to complete the treatments, which were administered in a span of about two weeks compared to traditional therapies which can take up to nine weeks. Severe toxicity was reported at 12 percent using the combination therapy, compared to upwards of 85 percent using conventional therapies.

“The good news here is that we improved their quality of life and did it safely,” said John Vargo, M.D., a radiation oncology resident at UPMC CancerCenter and one of the lead authors of the study.

“Unfortunately, outcomes using this approach are still challenging so the next part of our research will concentrate on continuing to find ways to improve outcomes by integrating additional novel systemic agents.”

September, 2014|Oral Cancer News|

Docetaxel regimen tops cisplatin in head and neck cancer

Source: www.cancernetwork.com
Author: Anna Azvolinsky, PhD

A phase II study has demonstrated that combining docetaxel-based chemoradiotherapy and the antibody cetuximab postoperatively in patients with high-risk squamous cell carcinoma of the head and neck led to improved disease-free and overall survival, with no unexpected toxicities. The results of the study were published in the Journal of Clinical Oncology.

Two-hundred and thirty-eight stage III and IV patients were randomized to receive radiation therapy (60 Gy) plus cetuximab and either cisplatin (30 mg/m2) or docetaxel (15 mg/m2) once per week as part of the Radiation Therapy Oncology Group (RTOG) 0234 clinical trial.

The 2-year overall survival (OS) was 69% in the cisplatin treatment arm and 79% in the docetaxel treatment arm. The 2-year disease-free survival (DFS) was 57% and 66% in the cisplatin and docetaxel arms, respectively.

Previously, two large phase III trials, the RTOG 9501 and the European Organisation for Research and Treatment of Cancer (EORTC) 22931 trials, both showed a small but significant survival benefit for postoperative head and neck cancer patients who received adjuvant radiation and chemotherapy concurrently, resulting in the incorporation of cisplatin in an adjuvant regimen for high-risk patients. The drawback was that adding cisplatin to radiation therapy increased toxicity. Many of these patients are not candidates for the combination therapy due to poor performance status, older age, and renal insufficiency. The purpose of the current trial was to test whether combining a molecular therapy such as cetuximab with chemotherapy would improve survival with a better toxicity profile, compared with radiation therapy plus chemotherapy.

After a median follow-up of 4.4 years, 48 patients in the cisplatin arm had a DFS event compared with 51 patients in the docetaxel arm. Cisplatin patients had a 24% reduction (P = .05) and docetaxel patients had a 31% reduction (P = .01) in the DFS failure rate compared with a historical control arm (the RTOG 9501 trial).

Patients who had p16-positive oropharynx tumors (43 of 54 patients) had improved survival compared with those who had p16-negative oropharynx disease.

The most common high-grade non-hematologic adverse events were mucositis, dysphagia, and skin rash, seen in both the cisplatin and docetaxel treatment arms. Patients in the cisplatin arm had a greater frequency of high-grade hematologic toxicities compared with those in the docetaxel arm (27.8% vs 14.2%, respectively). More patients in the docetaxel arm had toxicities deemed unacceptable by those conducting the trial (12.3% in the docetaxel arm vs 9.3% in the cisplatin arm).

Cetuximab is a chimeric human monoclonal antibody against the epidermal growth factor receptor (EGFR).

“The delivery of postoperative chemoradiotherapy (using cisplatin or docetaxel once per week plus 60 Gy radiation) with concurrent once-per-week cetuximab for patients with SCCHN [squamous cell carcinoma of the head and neck] who have high-risk pathologic features is feasible and tolerated with predictable toxicity. The radiation-docetaxel-cetuximab regimen shows particularly promising outcome with improvement in DFS and OS relative to RTOG historical controls and appears worthy of further investigation in high-risk patients with SCCHN,” concluded the authors.

Because the conclusions of this trial rely on a historical control comparison, these results need to be further validated in a phase III control-arm clinical trial. The docetaxel plus cetuximab regimen is currently being tested in a phase II/III clinical trial.

In an editorial, Amanda Psyrri, MD, PhD, and Urania Dafni, MD, both of the University of Athens in Greece, noted that, “In an era when next-generation sequencing is becoming increasingly available, identification of mutations that predict therapeutic response or resistance would be a major advance. Therefore, it seems mandatory that we focus our efforts at identifying an ‘EGFR sensitivity signature.’ Until then, it would seem wise not to conduct large phase III studies with cetuximab in unselected patient populations.”

An effective and well-tolerated strategy in recurrent and/or metastatic head and neck cancer: successive lines of active chemotherapeutic agents

Source: 7thspace.com
Author: staff

The combination platinum, 5-fluorouracil (5-FU) and cetuximab is the standard first-line regimen of recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC). Due to the toxicity of this treatment, alternative therapies are often offered to patients.

The aim of this study was to evaluate the overall survival obtained with a first line chemotherapy adapted to patients functional status and the administration of all active drugs within successive lines of chemotherapy.

Methods: This series included a total of 194 patients with recurrent and/or metastatic HNSCC treated from 2006 to 2011 in a single institution where the administration of successive lines of chemotherapies has been the standard clinical approach. Treatment was administered according to clinical practice guidelines.

Results: Most patients received at least two treatment lines.

Only 11 patients (6%) were treated with a combination of cisplatin, 5-FU and cetuximab in front line, but most patients received at least one platinum-based regimen (n = 154 patients, 78%); 162 (82%) received taxanes, 36 (18%) received 5-FU, 27 (14%) received capecitabine, 67 (34%) received methotrexate and 134 (68%) received cetuximab. The median overall survival was 9.8 months (95% CI: 8.1-11.4 months) and reached 13.1 months among the subgroup of 131 patients eligible for inclusion in a clinical trial.

Conclusion: The survival outcomes of patients treated in the first-line setting with chemotherapy regimens adapted to their functional status, followed by several subsequent regimens were comparable with published outcomes of patients treated by platinum, 5-FU and cetuximab.

Credits/Source: BMC Cancer 2014, 14:504

Lower radiation dose may be given to HPV-positive head and neck cancer patients

Source: Vanderbilt University
Published: June 19, 2014
By: Dagny Stuart

 

A new study suggests that lowering the dose of radiation therapy for some head and neck cancer patients may improve outcomes and cause fewer long-term side effects.

The research was presented by lead author Anthony Cmelak, M.D., professor of Radiation Oncology at Vanderbilt-Ingram Cancer Center, during the 50th annual meeting of the American Society of Clinical Oncology (ASCO), held May 30 to June 3 in Chicago.

The study focused on patients with newly diagnosed oropharyngeal cancers related to the human papilloma virus (HPV). More than two-thirds of new head and neck cancer patients have HPV-positive tumors and the number of these patients is on the rise. Cmelak’s prior study found that patients with HPV-positive oropharyngeal cancer have significantly longer survival rates than patients whose tumors are HPV negative.

For the new study, 80 HPV-positive patients with stage III, or IVa,b squamous cell cancer of the oropharynx received induction chemotherapy, including paclitaxel, cisplatin and cetuximab.

After chemotherapy, 62 of the patients showed no sign of cancer and were assigned to receive a 25 percent lower dose of intensity-modulated radiation therapy (IMRT) — an advanced technology that targets the radiation beam more accurately to treat the tumor without harming surrounding tissue. The rest of the patients received a standard IMRT dose. The drug cetuximab was also given to both groups of patients along with the IMRT treatment.

Two years after treatment, the survival for the low-dose IMRT patients was 93 percent. Those who did not have complete resolution of cancer following induction and went on to get full-dose radiation had an 87 percent two-year survival. Eighty percent of the low-dose patients and 65 percent of standard IMRT patients also showed no evidence of tumor recurrence. Ninety-six percent of those who had minimal or no smoking history had no evidence of tumor recurrence after two years following treatment, and long-term side effects were minimal.

The investigators concluded that patients with HPV-positive cancer who had excellent responses to induction chemotherapy followed by a reduced dose IMRT and cetuximab experienced high rates of tumor control and very low side effects, particularly for those with a minimal smoking history.

Treating tumors in the delicate head and neck region often causes side effects that can be troublesome and long-lasting, including difficulty swallowing, speech impairment, dry mouth, problems with taste and thyroid issues, so any therapy option that reduces these side effects can have an impact on patient quality of life.

“Treatment for head and neck cancer can be quite grueling, so it’s very encouraging to see we can safely dial back treatment for patients with less aggressive disease and an overall good prognosis, particularly for young patients who have many years to deal with long-term side effects,” said Cmelak.

He noted that lower-dose IMRT is not recommended for patients with HPV-negative cancer or larger tumors.

The authors note that further studies of reduced-dose IMRT in HPV-positive patients are warranted.

Funding was provided by The National Cancer Institute, a division of the National Institutes of Health (CDR0000665170).

* This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

 

June, 2014|Oral Cancer News|

Low-dose IMRT may be safe for patients with HPV-positive head and neck cancer

Source: www.oncologypractice.com
Author: Laura Nikolaides

Lower-dose radiation therapy may be safe for some patients with human papillomavirus (HPV)-positive oropharyngeal cancer, decreasing the risk of often long-term side effects, such as trouble swallowing, dry mouth, loss of taste, neck stiffness, and thyroid problems, investigators reported at the annual meeting of the American Society of Clinical Oncology.

Two-year overall survival and progression-free survival were 93% and 80%, respectively, among 62 patients with operable stage III/IVA HPV-positive oropharyngeal squamous carcinoma who received lower-dose intensity-modulated radiation therapy (IMRT) after clinical complete response to induction chemotherapy, reported Dr. Anthony Cmelak, professor of radiation oncology at Vanderbilt University, Nashville, Tenn., and medical director of the Vanderbilt-Ingram Cancer Center at Franklin.

Overall, the phase II study enrolled 90 patients, median age 57 years, who all received induction chemotherapy with paclitaxel, cisplatin, and cetuximab. The response to induction chemotherapy determined IMRT dose. The 62 patients who had a complete clinical response received a reduced dose (54 Gy) of IMRT, and the rest of the patients received standard dose IMRT (70 Gy). All patients received standard cetuximab along with radiation.

Two-year overall survival and progression-free survival for the higher-risk patients who received the standard dose of IMRT were 87% and 65% respectively. Among those patients receiving low-dose IMRT, survival was slightly higher for those with less than 10 pack-years of smoking and earlier-stage disease; in those patients 2-year progression-free and overall survival were 92% and 97%, respectively.

However, Dr. Cmelak does not yet recommend modifying regimens for patients with HPV-positive disease. “I don’t recommend using lower doses now, off study. Ultimately, we will need a large randomized trial,” he said. “This study represents one more piece of evidence that we need to look at the optimal regimen for both chemotherapy and radiation technique and dosage to minimize toxicities,” he added.

“We are not at the point where we know exactly how to treat patients with HPV-positive cancers. What we do know now is that there is a different biology to their tumors,” commented Dr. Gregory A. Masters, of the Helen F. Graham Cancer Center, Newark, Del., who attended the briefing but was not involved with the study. However, the study represents progress toward precision medicine, he said. “Most of what we have been doing over the last 49 years in oncology is escalating dosages. This is not necessarily always the right answer,” he added.

Experimental EGFR inhibitor added nothing but rash

Source: www.oncologypractice.com
Author: Neil Osterweil, Oncology Report Digital Network

The addition of the experimental targeted agent zalutumumab to primary curative chemoradiation for head and neck cancers did not improve locoregional control, disease-specific survival, or overall survival at 3 years of follow-up.

The only thing that zalutumumab added to therapy was a skin rash in the large majority of patients who received it, reported Dr. Jens Overgaard, of the department of experimental clinical oncology at Aarhus University, Denmark.

Response to zalutumumab, a monoclonal antibody targeted to the epidermal growth factor receptor (EGFR), was not related to tumor human papillomavirus 16 (HPV/p16) status or to chemoradiotherapy, Dr. Overgaard reported at the Multidisciplinary Head and Neck Cancer Symposium.

The results of the DAHANCA 19 trial echo those of the RTOG (Radiation Oncology Therapy Group) trial 0522, which found no benefit from the addition of the EGFR inhibitor cetuximab (Erbitux) to accelerated cisplatin-based chemoradiotherapy, said Dr. Paul Harari, an invited discussant from the University of Wisconsin, Madison.

“Where I think we have a lot of unanswered questions is acknowledging how little we actually understand about EGFR biology, despite now 40 years of progressive knowledge,” Dr. Harari said.

“We’re now seeing very clearly in molecular and clinical correlate studies that the more we suppress the EGFR, the more we see collateral overexpression of additional RTKs [receptor tyrosine kinases], including members of the HER family, such as HER-3, that enable an escape mechanism for tumors that become resistant to EGFR inhibition,” he said.

Dr. Overgaard and his colleagues in the Danish Head and Neck Cancer Group conducted an open-label, phase III trial in which 619 patients with nonmetastatic squamous cell carcinomas of the larynx, oropharynx, hypopharynx, or oral cavity were randomly assigned to received 66-68 Gy of accelerated radiotherapy with or without zalutumumab 8 mg/kg weekly, with the first dose given a week before the start of radiation. The radiation was given concomitantly with the radiosensitizer nimorazole and, in patients with involved lymph nodes, cisplatin.

A total of 301 patients who received zalutumumab and 307 controls were included in the final intention-to-treat analysis.

At 3-year follow-up, there were no significant differences in either the primary endpoint of locoregional control (76% in zalutumumab-treated patients and 77% of controls) or in the secondary endpoints of disease-specific survival (82% and 85%, respectively) or overall survival (72% and 79%), Dr. Overgaard reported at the symposium, cosponsored by the American Society for Radiation Oncology and the American Society of Clinical Oncology.

Overall, patients who were positive for the HPV/p16 biomarker fared better than p16-negative patients, with an odds ratio for the probability of local control in negative patients of 0.52 (95% confidence interval, 0.36-0.73; P value not reported).

However, regardless of HPV 16 status, the addition of zalutumumab made no difference in the primary endpoint.

In a proportional hazard analysis, factors significantly associated with worse outcomes included worse World Health Organization performance status, higher disease stage, nodal involvement, and HPV/p16 negative status.

Although zalutumumab was generally well tolerated, 94% of patients who received it developed a rash, and of this group, 29% had grade 3 or 4 rash. In all, 11% of patients assigned to zalutumumab had to stop the drug because of rash.

Note:
The trial was sponsored by the Danish Head and Neck Cancer Group. Dr. Overgaard reported having no financial disclosures. Dr. Harari has received research funding from Amgen.

March, 2014|Oral Cancer News|

PTEN loss, PIK3CA mutation predicted resistance to cetuximab in HNSCC

June 2, 2013
Source: Helio.com

 

CHICAGO — PTEN loss or PIK3CA mutation predicted resistance to treatment with cisplatin plus cetuximab in a cohort of patients with head and neck squamous cell carcinoma, according to phase 3 study results presented at the ASCO Annual Meeting.

“Cetuximab is the only targeted therapy in use in head and neck cancer, and although it prolongs survival, the effects are modest. For patients who receive [cetuximab] in the setting of metastatic or recurrent disease, median survival remains less than 1 year,” Barbara Burtness, MD, a medical oncologist at Fox Chase Cancer Center who specializes in head and neck cancers and a HemOnc Today Editorial Board member, said in an interview. “In colon cancer, patients are tested for KRAS mutations to detect patients with upfront resistance to cetuximab, but KRAS mutation is rare in head and neck cancer, and we haven’t had a biomarker to separate the sensitive from resistant patients.”

Burtness and colleagues compared cisplatin plus placebo vs. cisplatin plus cetuximab (Erbitux, Eli Lilly) in 117 patients. The researchers also assessed PIK3CA mutations and loss of PTEN expression in the cohort.

Results indicated that 34% of tumors studied had a loss of PTEN expression and 4% had PIK3CA mutations in the three hotspots studied.

Researchers did not observe any statistically significant differences in OS, PFS or overall response rates.

However, among patients with PIK3CA and PTEN expression, median PFS was 4.2 months for those assigned to cetuximab vs. 2.9 months for those assigned to placebo (adjusted P value=.07). Among patients with PIK3CA mutations but without PTEN expression, median survival was 4.6 months for those assigned to cetuximab and 3.5 months for those assigned to placebo.

“This study was limited by the small size of the original clinical trial, as well as by the fact that specimens were not available for all the patients, so the results are of borderline statistical significance,” Burtness said. “But if these data are corroborated in larger cohorts of cetuximab-treated patients, they would suggest that PTEN loss together with PIK3CA mutation could serve as a signature to identify patients who will not benefit from cetuximab therapy as it is currently given. The advent of PIK3 inhibitors could give us a new treatment strategy for these patients, potentially in combination with cetuximab.”

 

* This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

 

June, 2013|Oral Cancer News|

Erbitux add-on falls short in esophageal cancer

Source: www.medpagetoday.com
Author: Charles Bankhead, Staff Writer, MedPage Today

The addition of a targeted agent to definitive chemoradiation failed to improve survival in an unselected population with esophageal cancer, a randomized trial showed. In fact, patients who received cetuximab (Erbitux) with chemoradiation had significantly worse overall survival (OS) reflected in a 50% increase in the hazard versus chemoradiation alone, reported Thomas Crosby, MD, of Velindre Hospital in Cardiff, Wales, and colleagues.

Investigators could not find any subgroup of patients who benefited from cetuximab, they said in a presentation at the Gastrointestinal Cancers Symposium.

“The addition of cetuximab cannot be recommended to standard definitive chemoradiotherapy in the treatment of unselected patients with esophageal cancer,” Crosby said.

“The use of high-quality definitive chemoradiotherapy in the treatment of localized, poor-prognosis esophageal cancer was associated with excellent survival compared with previous radiotherapy and surgical series,” he added.

Randomized trials have shown that definitive (or primary) chemoradiation improves survival in localized esophageal cancer compared with a single treatment modality. In England, definitive chemoradiation has been used primarily for patients with localized disease that is unsuitable for surgery, Crosby said.

Add-on therapy with cetuximab has improved outcomes in other cancers, notably head and neck cancer and colorectal cancer. The findings provided a rationale for evaluating the addition of cetuximab to primary radiation therapy for localized esophageal cancer.

Crosby presented results of a randomized trial wherein patients with localized (stage I-III) esophageal cancer (less than 10 cm). Patients were excluded if they had celiac lymph-node involvement.

The patients received cisplatin-capecitabine (Xeloda) chemotherapy with or without cetuximab. After 6 weeks of chemotherapy, patients underwent definitive conformal radiation therapy at a total dose of 50 Gy in 25 fractions.

The trial had two stages. The first stage had a primary endpoint of treatment failure-free survival (TFFS), defined as alive at 6 months with no residual cancer in biopsy specimens and no evidence of disease progression outside the radiation therapy field. Secondary endpoints were toxicity, quality of life, overall survival (OS), and feasibility of recruitment. The first stage of the trial had an accrual target of 180 patients.

The trial’s second stage had a primary endpoint of OS and accrual to 420 patients.

However, the trial never reached second stage, but ended after a planned stage one analysis convinced the independent review committee that continued accrual to meet the primary endpoint would be futile.

Treatment and follow-up continued with enrolled patients, and the final analysis included 258 patients who had completed the 6-month assessment of disease status.

Crosby reported that patients randomized to conventional chemoradiation without cetuximab had a TFFS of 77% whereas the cetuximab group had a TFFS of 66%. All survival outcomes favored omission of cetuximab:

Median OS: 25.4 months versus 22.1 months
2-year survival: 56% versus 43.1%
Median progression-free survival: 19.4 months versus 15.9 months
The analysis showed a marked difference in median OS between patients who met the TFFS goal at 6 months and those who did not: 26.7 months versus 8.3 months.

Comparison of OS in the two arms yielded hazard ratio of 1.53 for the cetuximab arm versus chemoradiation only (P=0.035).

In addition to the inferior outcomes with cetuximab, addition of the targeted agent added to the toxicity burden. The cetuximab arm had an 81.4% incidence of grade 3 to 5 toxicity compared with 72.9% without cetuximab.

Patients who received cetuximab in addition to chemoradiation had significantly more grade 3 to 5 dermatologic toxicity (21.7% versus 3.9%, P<0.001) and metabolic/biochemical toxicity (24.0% versus 10.9%, P=0.005).

Additionally, the analysis revealed a trend toward more cardiac adverse events in the cetuximab arm (6.2% versus 1.6%, P=0.053).

The addition of cetuximab also adversely affected adherence to the treatment protocol. Patients in the cetuximab arm were significantly less likely to receive full doses of cisplatin (76.7% versus 89.9%, P=0.005), capecitabine (69.0% versus 85.3%, P=0.002), and radiation therapy (75.2% versus 86.0%, P=0.027).

Additionally, almost a third of patients did not receive the prescribed dose of cetuximab.

“Future strategies to improve the outcome of definitive chemoradiotherapy in esophageal cancer must focus on developing evidence-based biomarkers to select treatments and incorporating newer radiotherapy technologies and targeted systemic treatment to safely intensify treatment, including a higher radiotherapy dose,” Crosby said.

January, 2013|Oral Cancer News|

Scientists find new way to boost cancer drugs

Source: www.drbicuspid.com
Author: DrBicuspid Staff

Shutting down a specific pathway in cancer cells appears to improve the ability of common drugs to wipe those cells out, according to new research from scientists at Fox Chase Cancer Center (Cancer Discovery, January 2013, Vol. 3:1, pp. 96-111).

The new approach appears to enhance the tumor-killing ability of a commonly prescribed class of drugs that includes cetuximab (Erbitux), used to treat head and neck cancers. These drugs work by blocking the activity of the epidermal growth factor receptor (EGFR), which sits on the cell surface and senses cues from the environment, telling cancer cells to grow and divide, according to co-author Igor Astsaturov, MD, PhD, an attending physician in the department of medical oncology at Fox Chase.

In 2010, Dr. Astsaturov and his colleagues identified a pathway in the cell that, when blocked, completely suppressed EGFR activity. Interestingly, the pathway consists of a series of enzymes that, when working in concert, synthesize new molecules of cholesterol.

Working with cancer cells in the lab, the researchers inactivated a key gene in the cholesterol synthesis pathway, and found the cells became more vulnerable to treatment with cetuximab. The same was true in mice that lacked this particular pathway, according to Dr. Astsaturov.

“Most tumors are only moderately sensitive to inhibitors of EGFR, but when these tumors lack an essential gene in the cholesterol pathway, they become exquisitely sensitive to the anti-EGFR drugs,” he said. “The cancers literally melt away in mice.”

The researchers then removed one of the cholesterol genes from the mouse genome and saw that mice developed patchy, scaly skin. When they biopsied this affected skin, they saw no activity of the EGFR protein, reaffirming that shutting down cholesterol synthesis interrupts EGFR.

When the cholesterol biosynthesis pathway is blocked, the normal chain of events that creates a cholesterol molecule is interrupted, and cells accumulate intermediate products of cholesterol that block the normal movement of substances around the cell, according to the researchers. This cellular traffic jam makes it difficult for the cell to transport important components, such as EGFR, which has to move between the inside of the cell and its surface to function properly.

Eventually, researchers can design drugs or look for existing ones that block this cholesterol synthesis pathway, Dr. Astsaturov noted. For now, his lab is trying to uncover more details of how the pathway works, the role of each protein that is involved, and whether if, by blocking a protein, they can wipe out tumors in humans that evade current therapies.

January, 2013|Oral Cancer News|