Basal cell carcinoma is the most common cancer in the United States, with an incidence equal to that of all other cancers put together. The most common causes of basal cell carcinoma are environmental factors, including episodic sunlight exposure during childhood, radiation, some chemicals, and perhaps long-term sun exposure or tanning beds. There are also genetic risk factors that include fair skin and very rare disorders of DNA repair, for example xeroderma pigmentosum, that make people extremely sensitive to sunlight. In addition, there are other unidentified genes that may play a role in basal cell carcinoma. According to Allen E. Bale, M.D., a geneticist at the Department of Genetics, Yale University School of Medicine, an understanding of the possible genetic causes of basal cell carcinoma is an important step in finding new and effective treatments for the disease.
One extremely rare condition that Dr. Bale has studied extensively is Gorlin syndrome. This syndrome causes a specific predisposition to basal cell carcinoma but not to any other type of skin cancer. The estimated frequency of this syndrome is about 1 in 50,000.
“A patient with Gorlin syndrome can have tens to thousands of basal cell carcinomas over a lifetime,” says Dr. Bale. “Our research into that syndrome has really given us a great deal of insight into what’s going on from a genetic standpoint with sporadic basal cell carcinoma.”
Gorlin Syndrome and BCC
Gorlin syndrome is also known as the basal cell nevus syndrome and the nevoid basal cell carcinoma syndrome. The key features of Gorlin syndrome are multiple basal cell carcinomas, unusual cysts in the jaw bone called keratocysts, and pits of the palms and soles. (See photos.)
“Anybody who has all three of those features surely has this syndrome. The combination of any two of these feature would also be diagnostic as the syndrome,” says Dr. Bale. “People with Gorlin syndrome are also somewhat to very much taller than their sex-matched siblings. It’s not typically true gigantism, but they will be taller on the average. The implication is that the Gorlin syndrome gene plays a role in embryologic development and growth control in general.” (See Photo 1)
Dr. Bale’s research shows that Gorlin syndrome is associated with a mutation in the human homologue of the Drosophilia segment polarity gene patched (PTCH) on chromosome 9q22.3. Dr. Bale led the team that discovered the PTCH gene in 1996. This gene is also involved in the development of rhabdomyosarcoma, fibrosarcoma, meningioma, and medulloblastoma. An important implication is that the same treatments that might treat the skin cancer in this disease may treat much more aggressive or potentially lethal tumors.
Sporadic Cases
By studying blood and tumor samples from Gorlin syndrome families, Dr Bale’s team was able to positionally clone the gene responsible for this rare condition, determining that Gorlin syndrome results from heterozygous mutations in this gene. Dr. Bale also found that 50% of all children with Gorlin syndrome have what he refers to as “a sporadic case” because neither parent has the disease. “The parent’s DNA is normal and in the child with the Gorlin syndrome gene there’s a change in the coding sequence,” says Dr. Bale. Typically, these changes completely eradicate the function of the gene.
Among patients and families with typical Gorlin syndrome, Dr. Bale used direct sequencing to detect mutations in about 80% of cases. Dr. Bale suspects that the other 20% of cases are caused by other unidentified genetic mutations. Among patients and families with multiple or early-onset basal cell carcinomas without other features of Gorlin syndrome, virtually none had mutations on this gene. “These cases of early-onset or multiple basal cell carcinomas are quite unusual with no known etiology. We feel there is some other gene that also causes this phenotype,” says Dr. Bale. “It is very unusual to find patients from Gorlin syndrome families who have basal cell carcinomas with none of the other characteristics of the syndrome.”
Dr. Bale’s research also showed that with sporadic basal cell carcinoma, the same gene is mutated in almost all cases of the disease. Often, the mutations that occur change the DNA sequence from CC to TT. According to Dr. Bales, that is the signature mutation for ultraviolet B light (UVB), indicating that this mutation was induced by UVB.
“That mutation is consistent with our knowledge of what causes sporadic basal cell carcinomas,” explains Dr.Bale, “However, as many as two-thirds of the lesions we find would be hard to tie to UVB. We don’t know what causes them — perhaps cosmic rays, random chance, ultraviolet A light, some other agent, or another component of sunlight.”
GENE MUTATIONS
When Dr. Bale cloned the gene for Gorlin syndrome, he recognized that the PTCH gene is an inhibitor of the Hedgehog (Hh) signaling pathway that regulates development. According to Dr. Bale, if there is an inactivating mutation in the PTCH gene, that would activate the pathway downstream from PTCH.
“Fundamentally, we know that is what is happening. However, not quite 100% of basal cell carcinomas have inactivating mutations in PTCH, which implies other mutations,” asserts Dr. Bale. “In fact, almost all tumors that don’t have inactivating mutations in PTCH have activating mutations in the SMO gene. Thus, PTCH and SMO act as gatekeeper genes in basal cell carcinomas.” (See Figure 1.)
However, while mutating these genes is a necessary first step toward basal cell carcinoma, this mutation alone is probably not sufficient. “You have to get more mutations, and some of those that we know occur in P53 and RAS. Then you’re a little farther along this pathway,” explains Dr. Bale. “There are other genes not yet identified that are probably also necessary. Once cells have become fully malignant, there are probably yet another set of genes that differentiate them into a histopathologic subtype of basal cell carcinoma, and we don’t know these genes.”
DRUG DEVELOPMENT
If a mutation in these genes is needed to activate the Hh pathway to get basal cell carcinoma, a potential therapy for these tumors would be to target that pathway.
“Anything that would modulate or down-regulate the pathway would be a rational approach to treating or preventing basal cell carcinoma,” says Dr. Bale. “Since PTCH mutations cause abnormal activation of the Hh pathway, we would like to find drugs that switch off the pathway downstream from PTCH.”
One such drug is cyclopamine, which is derived from the corn lily that grows in the Rocky Mountains. In experiments that involved radiating mice with UV and then treating them with cyclopamine, the drug was reasonably effective in reducing the number of tumors. According to Dr. Bale, cyclopamine works by inhibiting the Hh pathway at the SMO gene, causing apoptosis in tumor cells. “Now this seems like it should be a great drug; it can be applied topically to tumors or given prophylactically to a person prone to tumors,” says Dr. Bale. “However, cyclopamine is not a drug that is currently on the market. And this is a drug that certainly has side effects, so I feel that it still needs development. But this is a drug that will probably be out on the market, if not for skin cancer, then maybe for medulloblastoma, which also are seen with Hh pathway activation.” (See Figure 2.)
Another drug that Dr. Bale is examining is sirolimus, also called rapamycin. Sirolimus is an immune modulator used in post-transplant patients, making it an unusual candidate for a cancer medication. According to Dr. Bale, the drug was shown to have anti-tumor activity against medulloblastoma seen in Gorlin syndrome.
Sirolimus antagonizes the transformed characteristics of cells with Gli activation. The Gli proteins are the effectors of Hh signaling and have been shown to be involved in cell-fate determination, proliferation and patterning in many cell types.
“We were already looking into inhibiting Gli function as a way of shutting off the pathway as far downstream as possible,” says Dr. Bale. “Our research showed that by over-expressing a protein called suppressor of fused, which is a natural inhibitor of Gli, we could limit the growth of tumor cells in culture. Sirolimus does something similar. We’re in the middle of a Phase I chemo-preventive clinical trial in people with basal cell carcinomas using sirolimus. We don’t have results yet, but we have some interesting intermediate data.”
A Study to Assess Sirolimus
The sirolimus study Dr. Bale is conducting involves an examination of molecular endpoints of sirolimus effect based on gene and protein expression in treated versus untreated skin. The study will also identify genes and proteins that are differentially expressed in Gorlin syndrome subjects when compared to controls pre-treatment. Use of targeted expression studies will assess the effects of sirolimus on an identified set of genes in vivo in Gorlin syndrome patients and controls. “The basic plan of this trial is different from a lot of clinical trials; it doesn’t have clinical endpoints because of the length of treatment required. So what we’re looking at is molecular endpoints of the effect — gene and protein expression in treated versus untreated skin.”
Dr Bale also acknowledged the contributions of the trial sponsors at the National Cancer Institute, and in particular Levy Kopelovich, Ph.D., and James Crowell. “Dr. Kopelovich’s thinking about Gorlin syndrome and many cancer predisposition syndromes is that even before tumors develop, there’s something going on in the skin that’s abnormal,” says Dr. Bale.
“He originally conceived the study to identify genes and proteins that are differentially expressed in basal cell nevus nevi and of Gorlin syndrome’s subjects versus controls at baseline before we treat them. We want to see what happens to targeted proteins and genes after you treat with sirolimus.”
Other Treatments for BCC
Several other drugs have been examined as possible treatments for basal cell carcinoma; however, some have been shown to be ineffective and others require more study. High enough doses of retinoids have been shown to prevent basal cell carcinomas in people with Gorlin syndrome, but patients will not stay on high-dose retinoids because of the side effects. Also, Dr. Bale’s research has not been able to show that retinoids affect the Hh pathway.
Though touted by some as possible treatments, green and black tea extracts have no effect on basal cell carcinomas.
However, imiquimod, an immune mediator, has been shown to induce apoptosis in tumor cells. “Imiquimod is an interesting approach because this is a drug that is not known to attack the molecular pathway that is necessary in the development of basal cell carcinomas, but it apparently is coming around from another angle to treat them,” explains Dr. Bale.
“Being a geneticist and coming at this from the molecular biology point of view, I want that magic bullet that treats exactly what’s wrong in the tumor. But right now I would say imiquimod is looking like a pretty good drug. I don’t think it can be used for prevention because I don’t think you can spread that over someone’s whole body, but for non-surgical treatment it can be very effective.”
Goal is Effective Treatment
While the primary focus of Dr. Bale’s work is the genetic basis of skin cancers, his goal is to develop effective treatments for basal cell carcinomas and other cancers.
“My work with hereditary cancer over the last 17 or 18 years provides an entrée into an understanding of what’s going on in sporadic cancer. We are starting out with a hereditary syndrome and clinically characterizing the syndrome, obtaining samples from patients, and identifying the genes involved,” says Dr. Bale.
“While these hereditary cancers are quite rare, what we learn from our research into hereditary cancers can be applied to sporadic cancer.
“What is really important from a public health point of view is the possibility of developing drugs that can be used for both hereditary and sporadic cancers.”
Dr. Bale is Associate Professor of Genetics, Director of the Cancer Genetics Program, Director of the DNA Diagnostics Program, and Director of the Medical Genetics Training Program at Yale University, New Haven, CT.
DISCLOSURE: Dr. Bale has no conflict of interest with any material discussed in this article.
Basal cell carcinoma is the most common cancer in the United States, with an incidence equal to that of all other cancers put together. The most common causes of basal cell carcinoma are environmental factors, including episodic sunlight exposure during childhood, radiation, some chemicals, and perhaps long-term sun exposure or tanning beds. There are also genetic risk factors that include fair skin and very rare disorders of DNA repair, for example xeroderma pigmentosum, that make people extremely sensitive to sunlight. In addition, there are other unidentified genes that may play a role in basal cell carcinoma. According to Allen E. Bale, M.D., a geneticist at the Department of Genetics, Yale University School of Medicine, an understanding of the possible genetic causes of basal cell carcinoma is an important step in finding new and effective treatments for the disease.
One extremely rare condition that Dr. Bale has studied extensively is Gorlin syndrome. This syndrome causes a specific predisposition to basal cell carcinoma but not to any other type of skin cancer. The estimated frequency of this syndrome is about 1 in 50,000.
“A patient with Gorlin syndrome can have tens to thousands of basal cell carcinomas over a lifetime,” says Dr. Bale. “Our research into that syndrome has really given us a great deal of insight into what’s going on from a genetic standpoint with sporadic basal cell carcinoma.”
Gorlin Syndrome and BCC
Gorlin syndrome is also known as the basal cell nevus syndrome and the nevoid basal cell carcinoma syndrome. The key features of Gorlin syndrome are multiple basal cell carcinomas, unusual cysts in the jaw bone called keratocysts, and pits of the palms and soles. (See photos.)
“Anybody who has all three of those features surely has this syndrome. The combination of any two of these feature would also be diagnostic as the syndrome,” says Dr. Bale. “People with Gorlin syndrome are also somewhat to very much taller than their sex-matched siblings. It’s not typically true gigantism, but they will be taller on the average. The implication is that the Gorlin syndrome gene plays a role in embryologic development and growth control in general.” (See Photo 1)
Dr. Bale’s research shows that Gorlin syndrome is associated with a mutation in the human homologue of the Drosophilia segment polarity gene patched (PTCH) on chromosome 9q22.3. Dr. Bale led the team that discovered the PTCH gene in 1996. This gene is also involved in the development of rhabdomyosarcoma, fibrosarcoma, meningioma, and medulloblastoma. An important implication is that the same treatments that might treat the skin cancer in this disease may treat much more aggressive or potentially lethal tumors.
Sporadic Cases
By studying blood and tumor samples from Gorlin syndrome families, Dr Bale’s team was able to positionally clone the gene responsible for this rare condition, determining that Gorlin syndrome results from heterozygous mutations in this gene. Dr. Bale also found that 50% of all children with Gorlin syndrome have what he refers to as “a sporadic case” because neither parent has the disease. “The parent’s DNA is normal and in the child with the Gorlin syndrome gene there’s a change in the coding sequence,” says Dr. Bale. Typically, these changes completely eradicate the function of the gene.
Among patients and families with typical Gorlin syndrome, Dr. Bale used direct sequencing to detect mutations in about 80% of cases. Dr. Bale suspects that the other 20% of cases are caused by other unidentified genetic mutations. Among patients and families with multiple or early-onset basal cell carcinomas without other features of Gorlin syndrome, virtually none had mutations on this gene. “These cases of early-onset or multiple basal cell carcinomas are quite unusual with no known etiology. We feel there is some other gene that also causes this phenotype,” says Dr. Bale. “It is very unusual to find patients from Gorlin syndrome families who have basal cell carcinomas with none of the other characteristics of the syndrome.”
Dr. Bale’s research also showed that with sporadic basal cell carcinoma, the same gene is mutated in almost all cases of the disease. Often, the mutations that occur change the DNA sequence from CC to TT. According to Dr. Bales, that is the signature mutation for ultraviolet B light (UVB), indicating that this mutation was induced by UVB.
“That mutation is consistent with our knowledge of what causes sporadic basal cell carcinomas,” explains Dr.Bale, “However, as many as two-thirds of the lesions we find would be hard to tie to UVB. We don’t know what causes them — perhaps cosmic rays, random chance, ultraviolet A light, some other agent, or another component of sunlight.”
GENE MUTATIONS
When Dr. Bale cloned the gene for Gorlin syndrome, he recognized that the PTCH gene is an inhibitor of the Hedgehog (Hh) signaling pathway that regulates development. According to Dr. Bale, if there is an inactivating mutation in the PTCH gene, that would activate the pathway downstream from PTCH.
“Fundamentally, we know that is what is happening. However, not quite 100% of basal cell carcinomas have inactivating mutations in PTCH, which implies other mutations,” asserts Dr. Bale. “In fact, almost all tumors that don’t have inactivating mutations in PTCH have activating mutations in the SMO gene. Thus, PTCH and SMO act as gatekeeper genes in basal cell carcinomas.” (See Figure 1.)
However, while mutating these genes is a necessary first step toward basal cell carcinoma, this mutation alone is probably not sufficient. “You have to get more mutations, and some of those that we know occur in P53 and RAS. Then you’re a little farther along this pathway,” explains Dr. Bale. “There are other genes not yet identified that are probably also necessary. Once cells have become fully malignant, there are probably yet another set of genes that differentiate them into a histopathologic subtype of basal cell carcinoma, and we don’t know these genes.”
DRUG DEVELOPMENT
If a mutation in these genes is needed to activate the Hh pathway to get basal cell carcinoma, a potential therapy for these tumors would be to target that pathway.
“Anything that would modulate or down-regulate the pathway would be a rational approach to treating or preventing basal cell carcinoma,” says Dr. Bale. “Since PTCH mutations cause abnormal activation of the Hh pathway, we would like to find drugs that switch off the pathway downstream from PTCH.”
One such drug is cyclopamine, which is derived from the corn lily that grows in the Rocky Mountains. In experiments that involved radiating mice with UV and then treating them with cyclopamine, the drug was reasonably effective in reducing the number of tumors. According to Dr. Bale, cyclopamine works by inhibiting the Hh pathway at the SMO gene, causing apoptosis in tumor cells. “Now this seems like it should be a great drug; it can be applied topically to tumors or given prophylactically to a person prone to tumors,” says Dr. Bale. “However, cyclopamine is not a drug that is currently on the market. And this is a drug that certainly has side effects, so I feel that it still needs development. But this is a drug that will probably be out on the market, if not for skin cancer, then maybe for medulloblastoma, which also are seen with Hh pathway activation.” (See Figure 2.)
Another drug that Dr. Bale is examining is sirolimus, also called rapamycin. Sirolimus is an immune modulator used in post-transplant patients, making it an unusual candidate for a cancer medication. According to Dr. Bale, the drug was shown to have anti-tumor activity against medulloblastoma seen in Gorlin syndrome.
Sirolimus antagonizes the transformed characteristics of cells with Gli activation. The Gli proteins are the effectors of Hh signaling and have been shown to be involved in cell-fate determination, proliferation and patterning in many cell types.
“We were already looking into inhibiting Gli function as a way of shutting off the pathway as far downstream as possible,” says Dr. Bale. “Our research showed that by over-expressing a protein called suppressor of fused, which is a natural inhibitor of Gli, we could limit the growth of tumor cells in culture. Sirolimus does something similar. We’re in the middle of a Phase I chemo-preventive clinical trial in people with basal cell carcinomas using sirolimus. We don’t have results yet, but we have some interesting intermediate data.”
A Study to Assess Sirolimus
The sirolimus study Dr. Bale is conducting involves an examination of molecular endpoints of sirolimus effect based on gene and protein expression in treated versus untreated skin. The study will also identify genes and proteins that are differentially expressed in Gorlin syndrome subjects when compared to controls pre-treatment. Use of targeted expression studies will assess the effects of sirolimus on an identified set of genes in vivo in Gorlin syndrome patients and controls. “The basic plan of this trial is different from a lot of clinical trials; it doesn’t have clinical endpoints because of the length of treatment required. So what we’re looking at is molecular endpoints of the effect — gene and protein expression in treated versus untreated skin.”
Dr Bale also acknowledged the contributions of the trial sponsors at the National Cancer Institute, and in particular Levy Kopelovich, Ph.D., and James Crowell. “Dr. Kopelovich’s thinking about Gorlin syndrome and many cancer predisposition syndromes is that even before tumors develop, there’s something going on in the skin that’s abnormal,” says Dr. Bale.
“He originally conceived the study to identify genes and proteins that are differentially expressed in basal cell nevus nevi and of Gorlin syndrome’s subjects versus controls at baseline before we treat them. We want to see what happens to targeted proteins and genes after you treat with sirolimus.”
Other Treatments for BCC
Several other drugs have been examined as possible treatments for basal cell carcinoma; however, some have been shown to be ineffective and others require more study. High enough doses of retinoids have been shown to prevent basal cell carcinomas in people with Gorlin syndrome, but patients will not stay on high-dose retinoids because of the side effects. Also, Dr. Bale’s research has not been able to show that retinoids affect the Hh pathway.
Though touted by some as possible treatments, green and black tea extracts have no effect on basal cell carcinomas.
However, imiquimod, an immune mediator, has been shown to induce apoptosis in tumor cells. “Imiquimod is an interesting approach because this is a drug that is not known to attack the molecular pathway that is necessary in the development of basal cell carcinomas, but it apparently is coming around from another angle to treat them,” explains Dr. Bale.
“Being a geneticist and coming at this from the molecular biology point of view, I want that magic bullet that treats exactly what’s wrong in the tumor. But right now I would say imiquimod is looking like a pretty good drug. I don’t think it can be used for prevention because I don’t think you can spread that over someone’s whole body, but for non-surgical treatment it can be very effective.”
Goal is Effective Treatment
While the primary focus of Dr. Bale’s work is the genetic basis of skin cancers, his goal is to develop effective treatments for basal cell carcinomas and other cancers.
“My work with hereditary cancer over the last 17 or 18 years provides an entrée into an understanding of what’s going on in sporadic cancer. We are starting out with a hereditary syndrome and clinically characterizing the syndrome, obtaining samples from patients, and identifying the genes involved,” says Dr. Bale.
“While these hereditary cancers are quite rare, what we learn from our research into hereditary cancers can be applied to sporadic cancer.
“What is really important from a public health point of view is the possibility of developing drugs that can be used for both hereditary and sporadic cancers.”
Dr. Bale is Associate Professor of Genetics, Director of the Cancer Genetics Program, Director of the DNA Diagnostics Program, and Director of the Medical Genetics Training Program at Yale University, New Haven, CT.
DISCLOSURE: Dr. Bale has no conflict of interest with any material discussed in this article.
Basal cell carcinoma is the most common cancer in the United States, with an incidence equal to that of all other cancers put together. The most common causes of basal cell carcinoma are environmental factors, including episodic sunlight exposure during childhood, radiation, some chemicals, and perhaps long-term sun exposure or tanning beds. There are also genetic risk factors that include fair skin and very rare disorders of DNA repair, for example xeroderma pigmentosum, that make people extremely sensitive to sunlight. In addition, there are other unidentified genes that may play a role in basal cell carcinoma. According to Allen E. Bale, M.D., a geneticist at the Department of Genetics, Yale University School of Medicine, an understanding of the possible genetic causes of basal cell carcinoma is an important step in finding new and effective treatments for the disease.
One extremely rare condition that Dr. Bale has studied extensively is Gorlin syndrome. This syndrome causes a specific predisposition to basal cell carcinoma but not to any other type of skin cancer. The estimated frequency of this syndrome is about 1 in 50,000.
“A patient with Gorlin syndrome can have tens to thousands of basal cell carcinomas over a lifetime,” says Dr. Bale. “Our research into that syndrome has really given us a great deal of insight into what’s going on from a genetic standpoint with sporadic basal cell carcinoma.”
Gorlin Syndrome and BCC
Gorlin syndrome is also known as the basal cell nevus syndrome and the nevoid basal cell carcinoma syndrome. The key features of Gorlin syndrome are multiple basal cell carcinomas, unusual cysts in the jaw bone called keratocysts, and pits of the palms and soles. (See photos.)
“Anybody who has all three of those features surely has this syndrome. The combination of any two of these feature would also be diagnostic as the syndrome,” says Dr. Bale. “People with Gorlin syndrome are also somewhat to very much taller than their sex-matched siblings. It’s not typically true gigantism, but they will be taller on the average. The implication is that the Gorlin syndrome gene plays a role in embryologic development and growth control in general.” (See Photo 1)
Dr. Bale’s research shows that Gorlin syndrome is associated with a mutation in the human homologue of the Drosophilia segment polarity gene patched (PTCH) on chromosome 9q22.3. Dr. Bale led the team that discovered the PTCH gene in 1996. This gene is also involved in the development of rhabdomyosarcoma, fibrosarcoma, meningioma, and medulloblastoma. An important implication is that the same treatments that might treat the skin cancer in this disease may treat much more aggressive or potentially lethal tumors.
Sporadic Cases
By studying blood and tumor samples from Gorlin syndrome families, Dr Bale’s team was able to positionally clone the gene responsible for this rare condition, determining that Gorlin syndrome results from heterozygous mutations in this gene. Dr. Bale also found that 50% of all children with Gorlin syndrome have what he refers to as “a sporadic case” because neither parent has the disease. “The parent’s DNA is normal and in the child with the Gorlin syndrome gene there’s a change in the coding sequence,” says Dr. Bale. Typically, these changes completely eradicate the function of the gene.
Among patients and families with typical Gorlin syndrome, Dr. Bale used direct sequencing to detect mutations in about 80% of cases. Dr. Bale suspects that the other 20% of cases are caused by other unidentified genetic mutations. Among patients and families with multiple or early-onset basal cell carcinomas without other features of Gorlin syndrome, virtually none had mutations on this gene. “These cases of early-onset or multiple basal cell carcinomas are quite unusual with no known etiology. We feel there is some other gene that also causes this phenotype,” says Dr. Bale. “It is very unusual to find patients from Gorlin syndrome families who have basal cell carcinomas with none of the other characteristics of the syndrome.”
Dr. Bale’s research also showed that with sporadic basal cell carcinoma, the same gene is mutated in almost all cases of the disease. Often, the mutations that occur change the DNA sequence from CC to TT. According to Dr. Bales, that is the signature mutation for ultraviolet B light (UVB), indicating that this mutation was induced by UVB.
“That mutation is consistent with our knowledge of what causes sporadic basal cell carcinomas,” explains Dr.Bale, “However, as many as two-thirds of the lesions we find would be hard to tie to UVB. We don’t know what causes them — perhaps cosmic rays, random chance, ultraviolet A light, some other agent, or another component of sunlight.”
GENE MUTATIONS
When Dr. Bale cloned the gene for Gorlin syndrome, he recognized that the PTCH gene is an inhibitor of the Hedgehog (Hh) signaling pathway that regulates development. According to Dr. Bale, if there is an inactivating mutation in the PTCH gene, that would activate the pathway downstream from PTCH.
“Fundamentally, we know that is what is happening. However, not quite 100% of basal cell carcinomas have inactivating mutations in PTCH, which implies other mutations,” asserts Dr. Bale. “In fact, almost all tumors that don’t have inactivating mutations in PTCH have activating mutations in the SMO gene. Thus, PTCH and SMO act as gatekeeper genes in basal cell carcinomas.” (See Figure 1.)
However, while mutating these genes is a necessary first step toward basal cell carcinoma, this mutation alone is probably not sufficient. “You have to get more mutations, and some of those that we know occur in P53 and RAS. Then you’re a little farther along this pathway,” explains Dr. Bale. “There are other genes not yet identified that are probably also necessary. Once cells have become fully malignant, there are probably yet another set of genes that differentiate them into a histopathologic subtype of basal cell carcinoma, and we don’t know these genes.”
DRUG DEVELOPMENT
If a mutation in these genes is needed to activate the Hh pathway to get basal cell carcinoma, a potential therapy for these tumors would be to target that pathway.
“Anything that would modulate or down-regulate the pathway would be a rational approach to treating or preventing basal cell carcinoma,” says Dr. Bale. “Since PTCH mutations cause abnormal activation of the Hh pathway, we would like to find drugs that switch off the pathway downstream from PTCH.”
One such drug is cyclopamine, which is derived from the corn lily that grows in the Rocky Mountains. In experiments that involved radiating mice with UV and then treating them with cyclopamine, the drug was reasonably effective in reducing the number of tumors. According to Dr. Bale, cyclopamine works by inhibiting the Hh pathway at the SMO gene, causing apoptosis in tumor cells. “Now this seems like it should be a great drug; it can be applied topically to tumors or given prophylactically to a person prone to tumors,” says Dr. Bale. “However, cyclopamine is not a drug that is currently on the market. And this is a drug that certainly has side effects, so I feel that it still needs development. But this is a drug that will probably be out on the market, if not for skin cancer, then maybe for medulloblastoma, which also are seen with Hh pathway activation.” (See Figure 2.)
Another drug that Dr. Bale is examining is sirolimus, also called rapamycin. Sirolimus is an immune modulator used in post-transplant patients, making it an unusual candidate for a cancer medication. According to Dr. Bale, the drug was shown to have anti-tumor activity against medulloblastoma seen in Gorlin syndrome.
Sirolimus antagonizes the transformed characteristics of cells with Gli activation. The Gli proteins are the effectors of Hh signaling and have been shown to be involved in cell-fate determination, proliferation and patterning in many cell types.
“We were already looking into inhibiting Gli function as a way of shutting off the pathway as far downstream as possible,” says Dr. Bale. “Our research showed that by over-expressing a protein called suppressor of fused, which is a natural inhibitor of Gli, we could limit the growth of tumor cells in culture. Sirolimus does something similar. We’re in the middle of a Phase I chemo-preventive clinical trial in people with basal cell carcinomas using sirolimus. We don’t have results yet, but we have some interesting intermediate data.”
A Study to Assess Sirolimus
The sirolimus study Dr. Bale is conducting involves an examination of molecular endpoints of sirolimus effect based on gene and protein expression in treated versus untreated skin. The study will also identify genes and proteins that are differentially expressed in Gorlin syndrome subjects when compared to controls pre-treatment. Use of targeted expression studies will assess the effects of sirolimus on an identified set of genes in vivo in Gorlin syndrome patients and controls. “The basic plan of this trial is different from a lot of clinical trials; it doesn’t have clinical endpoints because of the length of treatment required. So what we’re looking at is molecular endpoints of the effect — gene and protein expression in treated versus untreated skin.”
Dr Bale also acknowledged the contributions of the trial sponsors at the National Cancer Institute, and in particular Levy Kopelovich, Ph.D., and James Crowell. “Dr. Kopelovich’s thinking about Gorlin syndrome and many cancer predisposition syndromes is that even before tumors develop, there’s something going on in the skin that’s abnormal,” says Dr. Bale.
“He originally conceived the study to identify genes and proteins that are differentially expressed in basal cell nevus nevi and of Gorlin syndrome’s subjects versus controls at baseline before we treat them. We want to see what happens to targeted proteins and genes after you treat with sirolimus.”
Other Treatments for BCC
Several other drugs have been examined as possible treatments for basal cell carcinoma; however, some have been shown to be ineffective and others require more study. High enough doses of retinoids have been shown to prevent basal cell carcinomas in people with Gorlin syndrome, but patients will not stay on high-dose retinoids because of the side effects. Also, Dr. Bale’s research has not been able to show that retinoids affect the Hh pathway.
Though touted by some as possible treatments, green and black tea extracts have no effect on basal cell carcinomas.
However, imiquimod, an immune mediator, has been shown to induce apoptosis in tumor cells. “Imiquimod is an interesting approach because this is a drug that is not known to attack the molecular pathway that is necessary in the development of basal cell carcinomas, but it apparently is coming around from another angle to treat them,” explains Dr. Bale.
“Being a geneticist and coming at this from the molecular biology point of view, I want that magic bullet that treats exactly what’s wrong in the tumor. But right now I would say imiquimod is looking like a pretty good drug. I don’t think it can be used for prevention because I don’t think you can spread that over someone’s whole body, but for non-surgical treatment it can be very effective.”
Goal is Effective Treatment
While the primary focus of Dr. Bale’s work is the genetic basis of skin cancers, his goal is to develop effective treatments for basal cell carcinomas and other cancers.
“My work with hereditary cancer over the last 17 or 18 years provides an entrée into an understanding of what’s going on in sporadic cancer. We are starting out with a hereditary syndrome and clinically characterizing the syndrome, obtaining samples from patients, and identifying the genes involved,” says Dr. Bale.
“While these hereditary cancers are quite rare, what we learn from our research into hereditary cancers can be applied to sporadic cancer.
“What is really important from a public health point of view is the possibility of developing drugs that can be used for both hereditary and sporadic cancers.”
Dr. Bale is Associate Professor of Genetics, Director of the Cancer Genetics Program, Director of the DNA Diagnostics Program, and Director of the Medical Genetics Training Program at Yale University, New Haven, CT.
DISCLOSURE: Dr. Bale has no conflict of interest with any material discussed in this article.
