Melanoma, NRAS, G12D (c.35G>A)

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Expand Collapse Melanoma  - General Description Skin cancer is a malignant tumor that grows in the skin cells and accounts for more than 50 percent of all cancers. There are generally three different types of skin cancer: basal cell carcinoma, squamous cell carcinoma and melanoma.

Basal cell carcinoma and squamous cell carcinoma usually appear on sun-exposed areas of the body. Prognosis is generally good and both of these cancer types can usually be effectively treated through surgery, with a minority of cases requiring radiation treatment.

Melanoma is the most aggressive form of skin cancer and arises in the cells that produce pigment (color) in the skin. BRAF is the gene that is most frequently activated by mutation in this malignancy and the common BRAF V600E and V600K mutations have been associated with a more aggressive clinical course and shorter survival. Vemurafenib is a new and effective FDA-approved targeted agent that is available to treat unresectable or metastatic melanoma based on the presence of a BRAF V600E mutation. Preclinical data has indicated that the rare BRAF V600R mutation may also be sensitive to vemurafenib. Also, the BRAF L597R mutation has been found to confer sensitivity to downstream MEK inhibitors. Most recently, the combination of the BRAF inhibitor dabrafenib with the MEK inhibitor trametinib was approved by FDA for the treatment of patients with BRAF V600E or V600K mutations. While less frequent, mutations in cancer genes such as NRAS, MEK, PTEN, PIK3CA and KIT may provide opportunities for enrollment into ongoing clinical trials.

Skin cancer is a malignant tumor that grows in the skin cells and accounts for more than 50 percent of all cancers. There are generally three different types of skin cancer: basal cell carcinoma, squamous cell carcinoma and melanoma.

Basal cell carcinoma and squamous cell carcinoma usually appear on sun-exposed areas of the body. Prognosis is generally good and both of these cancer types can usually be effectively treated through surgery, with a minority of cases requiring radiation treatment.

Melanoma is the most aggressive form of skin cancer and arises in the cells that produce pigment (color) in the skin. BRAF is the gene that is most frequently activated by mutation in this malignancy and the common BRAF V600E and V600K mutations have been associated with a more aggressive clinical course and shorter survival. Vemurafenib is a new and effective FDA-approved targeted agent that is available to treat unresectable or metastatic melanoma based on the presence of a BRAF V600E mutation. Preclinical data has indicated that the rare BRAF V600R mutation may also be sensitive to vemurafenib. Also, the BRAF L597R mutation has been found to confer sensitivity to downstream MEK inhibitors. Most recently, the combination of the BRAF inhibitor dabrafenib with the MEK inhibitor trametinib was approved by FDA for the treatment of patients with BRAF V600E or V600K mutations. While less frequent, mutations in cancer genes such as NRAS, MEK, PTEN, PIK3CA and KIT may provide opportunities for enrollment into ongoing clinical trials.

Skin cancer is a malignant tumor that grows in the skin cells and accounts for more than 50 percent of all cancers. There are generally three different types of skin cancer: basal cell carcinoma, squamous cell carcinoma and melanoma.

Basal cell carcinoma and squamous cell carcinoma usually appear on sun-exposed areas of the body. Prognosis is generally good and both of these cancer types can usually be effectively treated through surgery, with a minority of cases requiring radiation treatment.

Melanoma is the most aggressive form of skin cancer and arises in the cells that produce pigment (color) in the skin. BRAF is the gene that is most frequently activated by mutation in this malignancy and the common BRAF V600E and V600K mutations have been associated with a more aggressive clinical course and shorter survival. Vemurafenib is a new and effective FDA-approved targeted agent that is available to treat unresectable or metastatic melanoma based on the presence of a BRAF V600E mutation. Preclinical data has indicated that the rare BRAF V600R mutation may also be sensitive to vemurafenib. Also, the BRAF L597R mutation has been found to confer sensitivity to downstream MEK inhibitors. Most recently, the combination of the BRAF inhibitor dabrafenib with the MEK inhibitor trametinib was approved by FDA for the treatment of patients with BRAF V600E or V600K mutations. While less frequent, mutations in cancer genes such as NRAS, MEK, PTEN, PIK3CA and KIT may provide opportunities for enrollment into ongoing clinical trials.

Skin cancer is a malignant tumor that grows in the skin cells and accounts for more than 50 percent of all cancers. There are generally three different types of skin cancer: basal cell carcinoma, squamous cell carcinoma and melanoma.

Basal cell carcinoma and squamous cell carcinoma usually appear on sun-exposed areas of the body. Prognosis is generally good and both of these cancer types can usually be effectively treated through surgery, with a minority of cases requiring radiation treatment.

Melanoma is the most aggressive form of skin cancer and arises in the cells that produce pigment (color) in the skin. BRAF is the gene that is most frequently activated by mutation in this malignancy and the common BRAF V600E and V600K mutations have been associated with a more aggressive clinical course and shorter survival. Vemurafenib is a new and effective FDA-approved targeted agent that is available to treat unresectable or metastatic melanoma based on the presence of a BRAF V600E mutation. Preclinical data has indicated that the rare BRAF V600R mutation may also be sensitive to vemurafenib. Also, the BRAF L597R mutation has been found to confer sensitivity to downstream MEK inhibitors. Most recently, the combination of the BRAF inhibitor dabrafenib with the MEK inhibitor trametinib was approved by FDA for the treatment of patients with BRAF V600E or V600K mutations. While less frequent, mutations in cancer genes such as NRAS, MEK, PTEN, PIK3CA and KIT may provide opportunities for enrollment into ongoing clinical trials.

PubMed ID's
21343559, 22798288, 20551065
Expand Collapse NRAS  - General Description
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NRAS is a gene that provides the code for making NRAS, a GTPase that converts GTP to GDP. This protein is part of the MAP kinase signaling cascade that relays chemical signals from the outside of the cell to the cell's nucleus, and is primarily involved in controlling cell division. When NRAS is attached (bound) to GDP, it is in its “off” position and can't send signals to the nucleus. But when a GTP molecule arrives and binds to NRAS, NRAS is activated and sends its signal, and then it converts the GTP into GDP and returns to the "off" position. HRAS and KRAS are other GTPases that are similar to NRAS.

When mutated, however, NRAS can act as an oncogene, causing normal cells to become cancerous. The mutations can shift the NRAS protein into the "on" position all the time. These NRAS mutations are said to be somatic, because instead of coming from a parent and being present in every cell (hereditary), they are acquired during the course of a person's life and are found only in cells that become cancerous.

Tumor mutation profiling performed clinically at the MGH Cancer Center has identified the highest incidence of NRAS mutations in melanoma (~30%), acute myeloid leukemia (~15%) and thyroid carcinoma (5-10%).

Source: Genetics Home Reference
NRAS (neuroblastoma RAS viral oncogene homolog) is a member of the closely related RAS gene family that also includes KRAS and HRAS. These RAS members are small GTPases that mediate extracellular signals to the downstream effectors RAF, PI3K and RALGDS. RAS members are involved in regulating diverse cellular processes including survival, proliferation and differentiation. While activating mutations in the RAS genes lead to sustained GTPase activation that contributes to oncogenesis, each oncogene exerts clear differences. Mutational hotspots in NRAS reside primarily in amino acid residues 12, 13 or 61 and function to suppress apoptosis.

Clinical tumor genotyping performed at the MGH Cancer Center has identified the highest incidence of NRAS mutations in melanoma (~30%), acute myeloid leukemia (~15%) and thyroid carcinoma (5-10%).

Source: Genetics Home Reference
PubMed ID's
18372904, 21779495
Expand Collapse G12D (c.35G>A)  in NRAS
The NRAS G12D mutation arises from a single nucleotide change (c.35G>A) and results in an amino acid substitution of the glycine (G) at position 12 by an aspartic acid (D).
The NRAS G12D mutation arises from a single nucleotide change (c.35G>A) and results in an amino acid substitution of the glycine (G) at position 12 by an aspartic acid (D).

Recent reports suggest that the presence of an NRAS mutation indicates poor prognosis in malignant melanoma, associated with shorter overall survival. Interestingly, patients with NRAS-mutant melanoma appear to respond better to high-dose IL2 (immunotherapy) than those having other genomic profiles.

The use of BRAF inhibitors (such as vemurafenib) is not advisable for the treatment of RAS-mutant positive melanoma patients. This is due to an unexpected and unfavorable activation of the MAP kinase cascade through an alternative signaling route that can increase tumor growth.

However, there is growing clinical evidence that NRAS mutant-positive melanoma may be responsive to pathway inhibitors at the MEK level. In a recent phase II clinical trial, 20% of the patients with NRAS Q61-mutant melanoma treated with MEK162 (a selective MEK inhibitor) achieved a partial response. Melanoma patients with an NRAS mutation at codon G12 or G13 have not yet been evaluated in clinical trial. Thus it is uncertain how these patients will respond to similar treatment strategies.

Preclinical evidence suggests that combining a CDK4/6 inhibitor with a MEK inhibitor might further improve responses.

Recent reports suggest that the presence of an NRAS mutation indicates poor prognosis in malignant melanoma, associated with shorter overall survival. Interestingly, patients with NRAS-mutant melanoma appear to respond better to high-dose IL2 (immunotherapy) than those having other genomic profiles.

The use of BRAF inhibitors (such as vemurafenib) is not advisable for the treatment of RAS-mutant positive melanoma patients. This is due to an unexpected and unfavorable activation of the MAP kinase cascade through an alternative signaling route that can increase tumor growth.

However, there is growing clinical evidence that NRAS mutant-positive melanoma may be responsive to pathway inhibitors at the MEK level. In a recent phase II clinical trial, 20% of the patients with NRAS Q61-mutant melanoma treated with MEK162 (a selective MEK inhibitor) achieved a partial response. Melanoma patients with an NRAS mutation at codon G12 or G13 have not yet been evaluated in clinical trial. Thus it is uncertain how these patients will respond to similar treatment strategies.

Preclinical evidence suggests that combining a CDK4/6 inhibitor with a MEK inhibitor might further improve responses.

PubMed ID's
21615881, 21788131, 21107323, 21576590, 23414587, 22997239, 20179705, 20130576, 18390968, 17699718, 16273091, 23414587, 22130161
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Your Matched Clinical Trials

Trial Matches: (D) - Disease, (G) - Gene, (M) - Mutation
Trial Status: Showing Results: 1-10 of 24 Per Page:
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Protocol # Title Location Status Match
NCT02327169 A Phase 1B Study of MLN2480 in Combination With MLN0128 or Alisertib, or Paclitaxel, or Cetuximab, or Irinotecan in Adult Patients With Advanced Nonhematologic Malignancies A Phase 1B Study of MLN2480 in Combination With MLN0128 or Alisertib, or Paclitaxel, or Cetuximab, or Irinotecan in Adult Patients With Advanced Nonhematologic Malignancies MGH Open DGM
NCT02296112 Trametinib in Treating Patients With Advanced Melanoma With BRAF Non-V600 Mutations Trametinib in Treating Patients With Advanced Melanoma With BRAF Non-V600 Mutations MGH Open DGM
NCT02637531 A Dose-Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of IPI-549 A Dose-Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of IPI-549 MGH Open D
NCT02110355 A Phase 1b/2a Study Evaluating AMG 232 in Metastatic Melanoma A Phase 1b/2a Study Evaluating AMG 232 in Metastatic Melanoma MGH Open D
NCT01714739 A Study of an Anti-KIR Antibody in Combination With an Anti-PD1 Antibody in Patients With Advanced Solid Tumors A Study of an Anti-KIR Antibody in Combination With an Anti-PD1 Antibody in Patients With Advanced Solid Tumors MGH Open D
NCT01325441 A Study of BBI608 Administered With Paclitaxel in Adult Patients With Advanced Malignancies A Study of BBI608 Administered With Paclitaxel in Adult Patients With Advanced Malignancies MGH Open D
NCT02228811 A Study of DCC-2701 in Participants With Advanced Solid Tumors A Study of DCC-2701 in Participants With Advanced Solid Tumors MGH Open D
NCT02471846 A Study of GDC-0919 and Atezolizumab Combination Treatment in Participants With Locally Advanced or Metastatic Solid Tumors A Study of GDC-0919 and Atezolizumab Combination Treatment in Participants With Locally Advanced or Metastatic Solid Tumors MGH Open D
NCT02082210 A Study of LY2875358 in Combination With Ramucirumab (LY3009806) in Participants With Advanced Cancer A Study of LY2875358 in Combination With Ramucirumab (LY3009806) in Participants With Advanced Cancer MGH Open D
NCT02320058 A Study to Evaluate Safety and Effectiveness in Patients With Melanoma That Has Spread to the Brain Treated With Nivolumab in Combination With Ipilimumab Followed by Nivolumab by Itself A Study to Evaluate Safety and Effectiveness in Patients With Melanoma That Has Spread to the Brain Treated With Nivolumab in Combination With Ipilimumab Followed by Nivolumab by Itself MGH Open D
Trial Status: Showing Results: 1-10 of 24 Per Page:
123Next »
Our Melanoma Team

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